Treatment of depression or generalized anxiety disorder

ABSTRACT

A pharmaceutical composition for treating a disorder that is treated by modulation of serotonergic neurotransmission comprising administering (7S,9aS)-cis-2-Benzo[d]isoxazol-3-yl-7-(3-pyrrolidin-1-ylmethyl-phenoxymethyl)-octahydro-pyrido-[1,2-a]pyrazine and sertraline is disclosed.

This application is a divisional of Ser. No. 09/403,892, filed Jan. 18,2000, now U.S. Pat. No. 6,525,048, which is a Section 371 National Stageof International Application Number PCT/IB99/00457, filed Mar. 18, 1999,which claims the benefit of U.S. Provisional Application Ser. No.60/081,237, filed Apr. 9, 1998.

BACKGROUND OF THE INVENTION

The present invention relates to novelaminomethylphenoxymethyl/benzisoxazole substituted azabicycliccompounds, to intermediates for their preparation, to pharmaceuticalcompositions containing them and to their medicinal use. The compoundsof the present invention include selective agonists and antagonists ofserotonin 1 (5-HT1) receptors, specifically, of one or both of the5-HT1A and 5-HT1D receptors. They are useful in treating or preventingmigraine, depression and other disorders for which a 5-HT1 agonist orantagonist is indicated.

European Patent Publication 434,561, published on Jun. 26, 1991, refersto 7-alkyl, alkoxy, and hydroxysubstituted-1-(4-substituted-1-piperazinyl)-naphthalenes. The compoundsare referred to as 5-HT1 agonists and antagonists useful for thetreatment of migraine, depression, anxiety, schizophrenia, stress andpain.

European Patent Publication 343,050, published on Nov. 23, 1989, refersto 7-unsubstituted, halogenated, and methoxysubstituted-1-(4-substituted-1-piper-azinyl)-naphthalenes as useful5-HT1A ligand therapeutics.

PCT publication WO 94/21619, published Sep. 29, 1994, refers tonaphthalene derivatives as 5-HT1 agonists and antagonists.

PCT publication WO 96/00720, published Jan. 11, 1996, refers to naphthylethers as useful 5-HT1 agonists and antagonists.

European Patent Publication 701,819, published Mar. 20, 1996, refers tothe use of 5-HT1 agonists and antagonists in combination with a 5-HTre-uptake inhibitor.

Glennon et al., refers to 7-methoxy-1-(1-piperazinyl)-naphthalene as auseful 5-HT1 ligand in their article “5-HT1D Serotonin Receptors”,Clinical Drug Res. Dev., 22, 25-36 (1991).

Glennon's article “Serotonin Receptors: Clinical Implications”,Neurscience and Behavioral Reviews, 14, 35-47 (1990), refers to thepharmacological effects associated with serotonin receptors includingappetite suppression, thermoregulation, cardiovascular/hypotensiveeffects, sleep, psychosis, anxiety, depression, nausea, emesis,Alzheimer's disease, Parkinson's disease and Huntington's disease.

World Patent Application WO 95/31988, published Nov. 30, 1995, refers tothe use of a 5-HT1D antagonist in combination with a 5-HT1A antagonistto treat CNS disorders such as depression, generalized anxiety, panicdisorder, agoraphobia, social phobias, obsessive-compulsive disorder,post-traumatic stress disorder, memory disorders, anorexia nervosa andbulimia nervosa, Parkinson's disease, tardive dyskinesias, endocrinedisorders such as hyperprolactinaemia, vasospasm (particularly in thecerebral vasculature) and hypertension, disorders of thegastrointestinal tract where changes in motility and secretion areinvolved, as well as sexual dysfunction.

G. Maura et al., J. Neurochem, 66 (1), 203-209 (1996), have stated thatadministration of agonists selective for 5-HT1A receptors or for both5-HT1A and 5-HT1D receptors might represent a great improvement in thetreatment of human cerebellar ataxias, a multifaceted syndrome for whichno established therapy is available.

European Patent Publication 666,261, published Aug. 9, 1995 refers tothiazine and thiomorpholine derivatives which are claimed to be usefulfor the treatment of cataracts.

SUMMARY OF THE INVENTION

The present invention relates to compounds of the formula

-   -   wherein R³, R⁴, and Z are selected, independently, from        hydrogen, halo (e.g., chloro, fluoro, bromo or iodo), (C₁-C₄)        alkyl optionally substituted with from one to three fluorine        atoms, (C₁-C₄)alkoxy optionally substituted with from one to        three fluorine atoms, and (C₁-C₄)alkoxy-(C₁-C₄)alkyl wherein        each of the alkyl moieties may optionally be substituted with        from one to three fluorine atoms;    -   W is —CH₂—O—(C₁-C₆) alkyl wherein the alkyl moiety can be        straight or branched;    -   or W is —CH₂NR¹R² wherein R¹ and R² are independently selected        from hydrogen and straight or branched (C₁-C₆)alkyl;    -   or R¹ and R², together with the nitrogen to which they are        attached, form a saturated four membered monocyclic ring or a        saturated or unsaturated nonaromatic five to seven membered        monocyclic ring or a saturated or unsaturated nonaromatic seven        to ten membered bicyclic ring which may optionally contain one        or two heteroatoms in addition to the nitrogen of NR¹R², wherein        said heteroatoms are independently selected from oxygen,        nitrogen and sulfur, and wherein from one to three of the ring        carbon atoms, or one of the ring nitrogen atoms, may optionally        and independently be substituted with straight or branched        (C₁-C₄) alkyl, straight or branched (C₁-C₆) alkoxy, straight or        branched (C₁-C₃) alkyl-(C₃-C₇) cycloalkyl, hydroxy, amino,        cyano, halo, aryl-(straight or branched (C₁-C₃) alkyl) or        heteroaryl-(straight or branched (C₁-C₃) alkyl), wherein said        aryl is selected from phenyl and naphthyl and said heteroaryl is        selected from oxazolyl, isoxazoyl, thiazolyl, isothiazolyl,        furanyl, pyrazolyl, pyrrolyl, tetrazolyl, triazolyl, thienyl,        imidazolyl, pyrazinyl, pyrazolyl, indolyl, isoindolyl,        pyrazinyl, cinnolinyl, pyridinyl and pyrimidinyl;    -   with the proviso that in any ring formed by NR¹R²: (a) there can        be no more than one ring oxygen atom; (b) there can be no        hydroxy, alkoxy, alkoxyalkyl, cyano, amino or alkylamino moiety        bonded directly to any ring nitrogen atom; and (c) no ring        carbon that is double bonded to another ring carbon and not part        of an aromatic ring system can be bonded to a ring oxygen atom        or ring nitrogen atom.

Examples of preferred compounds of the formula I are those having theabsolute stereochemical configuration defined as 7R,9aS-trans or as 7S,9aS-cis.

Examples of specific embodiments of this invention are the followingcompounds of the formula I and their pharmaceutically acceptable salts:

(7R,9as)-trans-1-{3-[2-(5-Fluoro-benzo[d]Isoxazol-3-yl)-octahydropyrido[1,2-a]pyrazin-7-ylmethoxy]-benzyl}-azetidin-3-ol;

(7R,9aS)-trans-2-(5-Fluoro-benzo[d]isoxazol-3-yl)-7-(3-morpholin-4-ylmethylphenoxymethyl)-octahydro-pyrido[1,2-a]pyrazine;

(7S,9as)-cis-1-(3-{1-[2-(Benzo[d]isoxazol-3-yl-methyl-amino)-ethyl]-6-methyl-piperidin-3-ylmethoxy}-benzyl)-azetidin-3-ol;

(7R,9aS)-trans-2-(4-Fluoro-benzo[d]isoxazol-3-yl)-7-(3-pyrrolidin-1-ylmethyl-phenoxymethyl)-octahydro-pyrido[1,2-a]pyrazine;

(7S,9aS)-cis-2-Benzo[d]isoxazol-3-yl-7-(3-pyrrolidin-1-ylmethyl-phenoxymethyl)-octahydro-pyrido-[1,2-a]pyrazine;

(7S,9aS)-cis-1-[3-(2-Benzo[d]isoxazol-3-yl-octahydro-pyrido[1,2-a]pyrazin-7-ylmethoxy)-benzyl]pyrrolidine-3,4-diol;

(7R,9aS)-trans-2-(5-Fluoro-benzo[d]isoxazol-3-yl)-7-(3-pyrrolidin-1-ylmethyl-phenoxymethyl)-octahydropyrido[1,2-a]pyrazine;

(7S,9aS)-cis-2-Benzo[d]isoxazol-3-yl-7-(2-methyl-5-pyrrolidin-1-ylmethyl-phenoxymethyl)-octahydro-pyrido[1,2-a]pyrazine;

(7S,9aS)-cis-2-Benzo[d]isoxazol-3-yl-7-(3-methoxy-5-pyrrolidin-1-ylmethyl-phenoxymethyl)-octahydro-pyrido[1,2-a]pyrazine;

(7S,9aS)-cis-2-Benzo[d]isoxazol-3-yl-7-(4-chloro-3-pyrrolidin-1-ylmethyl-phenoxymethyl)-octahydro-pyrido[1,2-a]pyrazine;

(7S,9aS)-cis-2-Benzo[d]isoxazol-3-yl-7-(4-pyrrolidin-1-ylmethyl-phenoxymethyl)-octahydro-pyrido[1,2-a]pyrazine;

(7S,9aS)-cis-7-(3-azetidin-1-ylmethyl-phenoxymethyl)-2-benzo[d]isoxazol-3-yl-octahydro-pyrido[1,2-a]pyrazine;

(7S,9aS)-cis-[3-(2-Benzo[d]isoxazol-3-yl-octahydro-pyrido[1,2-a]pyrazin-7-ylmethoxy)-benzyl]-cyclopropylmethyl-amine;

(7S,9aS)-cis-2-Benzo[d]isoxazol-3-yl-7-[3-(2-methoxymethyl-pyrrolidin-1-ylmethyl)-phenoxymethyl]-octahydro-pyrido[1,2-a]pyrazine;

(7S,9aS)-cis-[3-(2-Benzo[d]isoxazol-3-yl-octahydro-pyrido[1,2-a]pyrazin-7-ylmethoxy)-benzyl]-cyclopropyl-amine;

(7S,9aS)-cis-2-Benzo[d]isoxazol-3-yl-7-(3-pyrrolidin-1-ylmethyl-phenoxymethyl)-octahydro-pyrido[1,2-a]pyrazine;

(7S,9aS)-cis-2-Benzo[d]isoxazol-3-yl-7-[3-(4-ethyl-piperazin-1-ylmethyl)-phenoxymethyl]-octahydro-pyrido[1,2-a]pyrazine;

(7S,9aS)-cis-[3-(2-Benzo[d]isoxazol-3-yl-octahydro-pyrido[1,2-a]pyrazin-7-ylmethoxy)-benzyl]-cyclohexyl-amine;

(7S,9aS)-cis-1-[3-(2-Benzo[d]isoxazol-3-yl-octahydro-pyridol[1,2-a]pyrazin-7-ylmethoxy)-benzyl]-pyrrolidin-3-ol;

(7S,9aS)-cis-2-Benzo[d]isoxazol-3-yl-7-[3-(2,5-dimethyl-[pyrrolidin-1-ylmethyl)-phenoxymethyl-octahydro-pyrido[1,2-a]pyrazine;

(7S,9aS)-cis-2-Benzo[d]isoxazol-3-yl-7-[3-(2,5-dimethyl-pyrrolidin-1-ylmethyl)-phenoxymethyl]-octahydro-pyridol[1,2-a]pyrazine;

(7S,9aS)-cis-1-[3-(2-Benzo[d]isoxazol-3-yl-octahydro-pyrido[1,2-a]pyrazin-7-ylmethoxy)-benzyl]-pyrrolidine-3,4-diol;

(7S,9aS)-cis-1-[3-(2-Benzo[d]isoxazol-3-yl-octahydro-pyrido[1,2-a]pyrazin-7-ylmethoxy)-benzyl]-pyrrolidin-3-ol;

(7S,9aS)-cis-[3-(2-Benzo[d]isoxazol-3-yl-octahydro-pyrido[1,2-a]pyrazin-7-ylmethoxy)-benzyl]-isobutyl-amine;

(7S,9aS)-cis-Benzo[d]isoxazol-3-yl-methyl-{2-[2-methyl-5-(2-morpholin-4-ylmethyl-phenoxymethyl)-piperidin-1-yl]-ethyl}-amine;

(7S,9aS)-cis-2-Benzo[d]isoxazol-3-yl-7-(2-pyrrolidin-1-ylmethyl-phenoxymethyl)-octahydro-pyridol[1,2-a]pyrazine;

(7S,9aS)-cis-2-Benzo[d]isoxazol-3-yl-7-(4-morpholin-4-ylmethyl-phenoxymethyl)-octahydro-pyrido[1,2-a]pyrazine;

(7S,9aS)-cis-2-Benzo[d]isoxazol-3-yl-7-(4-pyrrolidin-1-ylmethyl-phenoxymethyl)-octahydro-pyridol[1,2-a]pyrazine;

(7R,9aS)-trans-2-(7-Fluoro-benzo[d]isoxazol-3-yl)-7-(3-pyrrolidin-1-ylmethyl-phenoxymethyl)-octahydro-pyrido[1,2-a]pyrazine;

(7R,9aS)-trans-2-(6-Fluoro-benzo[d]isoxazol-3-yl)-7-(3-pyrrolidin-1-ylmethyl-phenoxymethyl)-octahydro-pyrido[1,2-a]pyrazine;

(7R,9aS)-trans-2-(6,7-Difluoro-benzodIsoxazol-3-yl)-7-(3-pyrrolidin-1-ylmethyl-phenoxymethyl)-octahydro-pyrido[1,2-a]pyrazine;

(7R,9aS)-trans-3-{3-[2-(5-Fluoro-benzo[d]isoxazol-3-yl)-octahydro-pyrido[1,2-a]pyrazin-7-ylmethoxy]-benzyl}-3-aza-bicyclo[3.2.2]nonaneand;

(7R,9aS)-trans-2-(5-Fluoro-benzo[d]isoxazol-3-yl)-7-[3-Cis-octahydro-isoindol-2-ylmethyl)-phenoxymethyl]-octahydro-pyrido[1,2-a]pyrazine.

Other specfic embodiments of this invention are the following compoundsof the formula I and their pharmaceutically acceptable salts:

(7S,9aS)-trans-2-(5-Fluoro-benzo[d]isoxazol-3-yl)-7-(2-pyrrolidin-1-ylmethyl-phenoxymethlthyl)-octahydro-pyrido[1,2-a]pyrazine;

(7S,9aS)-trans-2-(5-Chloro-benzo[d]isoxazol-3-yl)-7-(3-pyrrolidin-1-ylmethyl-phenoxymethyl)-octahydro-pyrido[1,2-a]pyrazine;

(7S,9aS)-trans-2-(5-Methyl-benzo[d]isoxazol-3-yl)-7-(3-pyrrolidin-1-ylmethyl-phenoxymethyl)-octahydro-pyrido[1,2-a]pyrazine;

(7S,9aS)-trans-2-Benzo[d]isoxazol-3-yl)-7-(2-pyrrolidin-1-ylmethyl-phenoxymethyl)-octahydro-pyrido[1,2-a]pyrazine;

(7R,9aS)-cis-2-Benzo[d]isoxazol-3-yl)-7-(2-pyrrolidin-1-ylmethyl-phenoxymethyl)-octahydro-pyrido[1,2-a]pyrazine;

(7S,9aS)-trans-2-(5-Fluoro-benzo[d]isoxazol-3-yl)-7-(2-morpholin-4-ylmethyl-phenoxymethyl)-octahydro-pyrido[1,2-a]pyrazine;

(7S,9aS)-trans-2-(5-Fluoro-benzo[d]isoxazol-3-yl)-7-(4-morpholin-4-ylmethyl-phenoxymethyl)-octahydro-pyrido[1,2-a]pyrazine;

(7R,9aS)-trans-2-(2-Methoxy-benzo[d]isoxazol-3-yl)-7-(3-pyrrolidin-1-ylmethyl-phenoxymethyl)-octahydro-pyrido[1,2-a]pyrazine;

(7S,9aS)-cis-2-(5-Methoxy-benzo[d]isoxazol-3-yl)-7-(3-pyrrolidin-1-ylmethyl-phenoxymethyl)-octahydro-pyrido[1,2-a]pyrazine;

(7R,9aS)-trans-2-(5-Fluoro-benzo[d]isoxazol-3-yl)-7-(3-(2-methoxymethyl-pyrrolidin-1-ylmethyl-phenoxymethyl)-octahydro-pyrido[1,2-a]pyrazine;

(7R,9aS)-trans-2-(5-Fluoro-benzo[d]isoxazol-3-yl)-7-[3-(2-methoxymethyl-pyrrolidin-1-ylmethyl-phenoxymethyl)-octahydro-pyrido[1,2-a]pyrazine;

(7R,9aS)-trans-2-(5-Fluoro-benzo[d]isoxazol-3-yl)-7-[3-(2-methoxymethyl-piperidin-1-ylmethyl-phenoxymethyl)-octahydro-pyrido[1,2-a]pyrazine;and

(7R,9aS)-trans-2-(5-Fluoro-benzo[d]isoxazol-3-yl)-7-[3-(3-methoxymethyl-piperidin-1-ylmethyl)-phenoxymethyl]-octahydro-pyrido[1,2-a].

The present invention also relates to a pharmaceutical composition fortreating a disorder or condition selected from hypertension, depression(e.g., depression in cancer patients, depression in Parkinson'spatients, postmyocardial infarction depression, subsyndromal symptomaticdepression, depression in infertile women, pediatric depression, majordepression, single episode depression, recurrent depression, child abuseinduced depression, and post partum depression), generalized anxietydisorder, phobias (e.g., agoraphobia, social phobia and simple phobias),posttraumatic stress syndrome, avoidant personality disorder, prematureejaculation, eating disorders (e.g., anorexia nervosa and bulimianervosa), obesity, chemical dependencies (e.g., addictions to alcohol,cocaine, heroin, phenobarbital, nicotine and benzodiazepines), clusterheadache, migraine, pain, Alzheimer's disease, obsessive-compulsivedisorder, panic disorder, memory disorders (e.g., dementia, amnesticdisorders, and age-related cognitive decline (ARCD)), Parkinson'sdiseases (e.g., dementia in Parkinson's disease, neuroleptic-inducedparkinsonism and tardive dyskinesias), endocrine disorders (e.g.,hyperprolactinaemia), vasospasm (particularly in the cerebralvasculature), cerebellar ataxia, gastrointestinal tract disorders(involving changes in motility and secretion), negative symptoms ofschizophrenia, premenstrual syndrome, fibromyalgia syndrome, stressincontinence, Tourette's syndrome, trichotillomania, kleptomania, maleimpotence, cancer (e.g., small cell lung carcinoma), chronic paroxysmalhemicrania and headache (associated with vascular disorders) in amammal, preferably a human, comprising an amount of a compound of theformula I or a pharmaceutically acceptable salt thereof effective intreating such disorder or condition and a pharmaceutically acceptablecarrier.

The present invention also relates to a pharmaceutical composition fortreating a disorder or condition that can be treated by modulatingserotonergic neurotransmission in a mammal, preferably a human,comprising an amount of a compound of the formula I, or apharmaceutically acceptable salt thereof, effective in treating suchdisorder or condition and a pharmaceutically acceptable carrier.Examples of such disorders and conditions are those enumerated in thepreceding paragraph.

The present invention also relates to a method for treating a disorderor condition selected from hypertension, depression (e.g., depression incancer patients, depression in Parkinson's patients, postmyocardialinfarction depression, subsyndromal symptomatic depression, depressionin infertile women, pediatric depression, major depression, singleepisode depression, recurrent depression, child abuse induceddepression, and post partum depression), generalized anxiety disorder,phobias (e.g. agoraphobia, social phobia and simple phobias),posttraumatic stress syndrome, avoidant personality disorder, prematureejaculation, eating disorders (e.g., anorexia nervosa and bulimianervosa), obesity, chemical dependencies (e.g., addictions to alcohol,cocaine, heroin, phenobarbital, nicotine and benzodiazepines), clusterheadache, migraine, pain, Alzheimer's disease, obsessive-compulsivedisorder, panic disorder, memory disorders (e., dementia, amnesticdisorders, and age-related cognitive decline (ARCD)), Parkinson'sdiseases (e.g., dementia in Parkinson's disease, neuroleptic-inducedparkinsonism and tardive dyskinesias), endocrine disorders (e.g.,hyperprolactinaemia), vasospasm (particularly in the cerebralvasculature), cerebellar ataxia, gastrointestinal tract disorders(involving changes in motility and secretion), negative symptoms ofschizophrenia, premenstrual syndrome, fibromyalgia syndrome, stressincontinence, Tourette's syndrome, trichotillomania, kleptomania, maleimpotence, cancer, (e.g., small cell lung carcinoma), chronic paroxysmalhemicrania and headache (associated with vascular disorders) in amammal, preferably a human, comprising administering to a mammal in needof such treatment an amount of a compound of the formula I, or apharmaceutically acceptable salt thereof, that is effective in treatingsuch disorder or condition.

The present invention also relates to a method for treating a disorderor condition that can be treated by modulating serotonergicneurotransmission in a mammal, preferably a human, comprisingadministering to a mammal in need of such treatment an amount of acompound of the formula I, or a pharmaceutically acceptable saltthereof, that is effective in treating such disorder or condition.

The present invention also relates to a pharmaceutical composition fortreating a disorder or condition selected from hypertension, depression(e.g. depression in cancer patients, depression in Parkinson's patients,postmyocardial infarction depression, subsyndromal symptomaticdepression, depression in infertile women, pediatric depression, majordepression, single episode depression, recurrent depression, child abuseinduced depression, and post partum depression), generalized anxietydisorder, phobias (e.g., agoraphobia, social phobia and simple phobias),posttraumatic stress syndrome, avoidant personality disorder, prematureejaculation, eating disorders (e.g., anorexia nervosa and bulimianervosa), obesity, chemical dependencies (e.g., addictions to alcohol,cocaine, heroin, phenobarbital, nicotine and benzodiazepines), clusterheadache, migraine, pain, Alzheimer's disease, obsessive-compulsivedisorder, panic disorder, memory disorders (e.g. dementia, amnesticdisorders, and age-related cognitive decline (ARCD)), Parkinson'sdiseases (e.g., dementia in Parkinson's disease, neuroleptic-inducedparkinsonism and tardive dyskinesias), endocrine disorders (e.g.,hyperprolactinaemia), vasospasm (particularly in the cerebralvasculature), cerebellar ataxia, gastrointestinal tract disorders(involving changes in motility and secretion), negative symptoms ofschizophrenia, premenstrual syndrome, fibromyalgia syndrome, stressincontinence, Tourette's syndrome, trichotillomania, kleptomania, maleimpotence, cancer (e.g., small cell lung carcinoma), chronic paroxysmalhemicrania and headache (associated with vascular disorders) in amammal, preferably a human, comprising a serotonin 1A receptorantagonizing or agonizing effective amount, or a serotonin iD receptorantagonizing effective amount, of a compound of the formula I, or apharmaceutically acceptable salt thereof, and a pharmaceuticallyacceptable carrier.

The present invention also relates to a pharmaceutical composition fortreating a disorder or condition that can be treated by modulatingserotonergic neurotransmission in a mammal, preferably a human,comprising a serotonin 1A receptor antagonizing or agonizing effectiveamount, or a serotonin 1D receptor antagonizing effective amount, of acompound of the formula I, or a pharmaceutically acceptable saltthereof, and a pharmaceutically acceptable carrier.

The present invention also relates to a method for treating a disorderor condition selected from hypertension, depression (e.g., depression incancer patients, depression in Parkinson's patients, postmyocardialinfarction depression, subsyndromal symptomatic depression, depressionin infertile women, pediatric depression, major depression, singleepisode depression, recurrent depression, child abuse induceddepression, and post partum depression), generalized anxiety disorder,phobias (e.g., agoraphobia, social phobia and simple phobias),posttraumatic stress syndrome, avoidant personality disorder, sexualdysfunction (e.g., premature ejaculation), eating disorders (e.g.,anorexia nervosa and bulimia nervosa), obesity, chemical dependencies(e.g., addictions to alcohol, cocaine, heroin, phenobarbital, nicotineand benzodiazepines), cluster headache, migraine, pain, Alzheimer'sdisease, obsessive-compulsive disorder, panic disorder, memory disorders(e.g., dementia, amnestic disorders, and age-related cognitive decline(ARCD)), Parkinson's diseases (e.g., dementia in Parkinson's disease,neuroleptic-induced parkinsonism and tardive dyskinesias), endocrinedisorders (e.g., hyperprolactinaemia), vasospasm (particularly in thecerebral vasculature), cerebellar ataxia, gastrointestinal tractdisorders (involving changes in motility and secretion), negativesymptoms of schizophrenia, premenstrual syndrome, fibromyalgia syndrome,stress incontinence, Tourette's syndrome, trichotillomania, kleptomania,male impotence, cancer (e.g., small cell lung carcinoma), chronicparoxysmal hemicrania and headache (associated with vascular disorders)in a mammal, preferably a human, comprising administering to a mammalrequiring such treatment a serotoninn 1A receptor antagonizing oragonizing effective amount, or a serotonin 1D receptor antagonizingeffective amount, of a compound of the formula I or a pharmaceuticallyacceptable salt thereof.

The present invention also relates to a method for treating a disorderor condition that can be treated by modulating serotonergicneurotransmission in a mammal, preferably a human, comprisingadministering to a mammal requiring such treatment a serotonin 1Areceptor antagonizing or agonizing effective amount, or a serotonin 1Dreceptor antagonizing effective amount, of a compound of the formula Ior a pharmaceutically acceptable salt thereof.

The present invention relates to a pharmaceutical composition fortreating a condition or disorder that can be treated by modulatingserotonergic neurotransmission in a mammal, preferably a human,comprising:

a) a pharmaceutically acceptable carrier;

b) a compound of the formula I or a pharmaceutically acceptable saltthereof; and

c) a 5-HT re-uptake inhibitor, preferably sertraline, or apharmaceutically acceptable salt thereof;

wherein the amount of the active compounds (i.e., the compound offormula I and the 5-HT re-uptake inhibitor) are such that thecombination is effective in treating such disorder or condition.

The present invention also relates to a method for treating a disorderor condition that can be treated by modulating serotonergicneurotransmission in a mammal, preferably a human, comprisingadministering to a mammal requiring such treatment:

a) a compound of the formula I, defined above, or a pharmaceuticallyacceptable salt thereof; and

b) a 5-HT re-uptake inhibitor, preferably sertraline, or apharmaceutically acceptable salt thereof;

wherein the amounts of the active compounds (i.e., the compound offormula I and the 5-HT re-uptake inhibitor) are such that thecombination is effective in treating such disorder or condition.

The present invention also relates to a method for treating a disorderor condition that can be treated by modulating serotonergicneurotransmission in a mammal, preferably a human, comprisingadministering to said mammal requiring such treatment:

a) a 5-HT1A agonist or antagonist or a pharmaceutically acceptable saltthereof; and

b) a 5-HT1D antagonist of formula I or a pharmaceutically acceptablesalt thereof;

wherein the amounts of each active compound (i.e., the 5-HT1A agonist orantagonist and the 5-HT1D antagonist) are such that the combination iseffective in treating such disorder or condition.

The present invention also relates to a pharmaceutical composition fortreating a disorder or condition that can be treated by modulatingserotonergic neurotransmission in a mammal, preferably a human,comprising:

a) a 5-HT1A agonist or antagonist or a pharmaceutically acceptable saltthereof; and

b) a 5-HT1D antagonist of formula I or a pharmaceutically acceptablesalt thereof;

wherein the amounts of each active compound (i.e., the 5-HT1A agonist orantagonist and the 5-HT1D antagonist) are such that the combination iseffective in treating such disorder or condition.

This invention also relates to the pharmaceutically acceptable acidaddition salts of the compounds of formula I. Examples ofpharmaceutically acceptable acid addition salts of the compounds offormula I are the salts of hydrochloric acid, p-toluenesulfonic acid,fumaric acid, citric acid, succinic acid, salicylic acid, oxalic acid,hydrobromic acid, phosphoric acid, methanesulfonic acid, tartaric acid,malate, di-p-toluoyl tartaric acid, and mandelic acid.

Unless otherwise indicated, the term “halo”, as used herein, includesfluoro, chloro, bromo and iodo.

Unless otherwise indicated, the term “alkyl”, as used herein, may bestraight, branched or cyclic, and may include straight and cyclicmoieties as well as branched and cyclic moieties.

The term “treatment”, as used herein, refers to reversing, alleviating,inhibiting the progress of, or preventing the disorder or condition towhich such term applies, or one or more symptoms of such condition ordisorder. The term “treatment”, as used herein, refers to the act oftreating, as “treating” is defined immediately above.

The compounds of formula I may have optical centers and therefore mayoccur in different enantiomeric configurations. The invention includesall enantiomers, diastereomers, and other stereoisomers of suchcompounds of formula I, as well as racemic and other mixtures thereof.

The present invention also relates to all radiolabelled forms of thecompounds of the formula I. Preferred radiolabelled compounds of formulaI are those wherein the radiolabels are selected from as ³H, ¹¹C, ¹⁴C,¹⁸F, ¹²³I and ¹²⁵I. Such radiolabelled compounds are useful as researchand diagnostic tools in metabolism pharmacokinetics studies and inbinding assays in both animals and man.

“Modulating serotonergic neurotransmission,” as used herein, refers toincreasing or improving, or decreasing or retarding the neuronal processwhereby serotonin is released by a pre-synaptic cell upon excitation andcrosses the synapse to stimulate or inhibit the post-synaptic cell.

“Chemical dependency,” as used herein, means an abnormal craving ordesire for, or an addiction to a drug. Such drugs are generallyadministered to the affected individual by any of a variety of means ofadministration, including oral, parenteral, nasal or by inhalation.Examples of chemical dependencies treatable by the methods of thepresent invention are dependencies on alcohol, nicotine, cocaine,heroin, phenolbarbitol, and benzodiazepines (e.g., Valium (trademark)).“Treating a chemical dependency,” as used herein, means reducing oralleviating such dependency.

Sertraline,(1S-cis)-4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydro-N-methyl-1-naphthalenamine,as used herein has the chemical formula C₁₇H₁₇NCl₂ and the followingstructural formula

Its synthesis is described in U.S. Pat. No. 4,536,518, assigned toPfizer Inc. Sertraline hydrochloride is useful as an antidepressant andanorectic agent, and is also useful in the treatment of depression,chemical dependencies, anxiety obsessive compulsive disorders, phobias,panic disorder, post traumatic stress disorder, and prematureejaculation.

This invention also relates to compounds of the formula

wherein the stereochemistry is either (7R,9aS)-trans or (7S, 9aS)-cis;

T is selected from HOCH₂—, HC(═O)—, H₃CO₂SOCH₂—, —CH₂NR¹R², straight orbranched (C₁-C₆)alkoxy, and

wherein Z is defined as in the definition of compounds of the formula I;and

V is selected from hydrogen, t-butoxycarbonyl, groups having the formula

wherein R³ and R⁴ are selected, independently, from hydrogen, chloro,fluoro, methyl and methoxy, and groups having the formula

wherein R³ and R⁴ are defined as above and the oximino moiety may besyn, anti, or a mixture of syn and anti isomers.

Such compounds are useful in the synthesis of compounds of the formulaI.

Examples of specific compounds of the formula G are the following:

7R,9aS)-trans-7-(3-methoxycarbonylphenoxymethyl)-octahydro-pyrido-1,2-a]pyrazine-2-carboxylicacid tert-butyl ester;

(7R,9aS)-trans-7-(3-hydroxymethylphenoxymethyl)-octahydro-pyrido-[1,2-a]pyrazine-2-carboxylicacid tert-butyl ester;

(7R,9aS)-trans-7-(3-pyrrolidin-1-ylmethyl-phenoxymethyl)-octahydro-pyrido[1,2-a]pyrazine-2-carboxylicacid tert-butyl ester;

(7R,9aS)-trans-3-(3-pyrrolidin-1-ylmethyl-phenoxymethyl)-octahydro-quinazolizinedihydrochloride and mineral bis-salts thereof;

(7R,9aS)-trans-[2-(5-fluoro-benzo[d]isoxazol-3-yl)-octahydro-pyrido-1,2-a]pyrazin-7-yl]-methanol;

(7S,9aS)-trans-3-[2-(5-fluoro-benzo[d]isoxazol-3-yl)-octahydro-pyrido[1,2-a]pyrazin-7-ylmethoxy]-benzoicacid methyl ester;

(7R,9aS)-trans-{3-[2-(5-fluoro-benzo[d]isoxazol-3-yl)-octahydro-pyrido[1,2-a]pyrazin-7-ylmethoxy]-phenyl}-methanol;

(7R,9aS)-trans-{3-[2-(5-fluoro-benzo[d]isoxazol-3-yl)-octahydro-pyrido[1,2-a]pyrazin-7-ylmethoxy]-phenyl}-methanolmethane sulfonate;

(7S,9aS)-cis-7-(3-methoxycarbonyl-phenoxymethyl)-octahydro-pyrido[1,2-a]pyrazine-2-carboxylicacid tert-butyl ester;

(7S,9aS)-cis-{2-[5-(3-hydroxymethyl-phenoxymethyl)-2-methyl-piperidin-1-yl]ethyl}-methyl-carbamicacid tert-butyl ester;

(7S,9aS)-cis-3-(2-Benzo[d]isoxazol-3-yl-octahydro-pyrido[1,2-a]pyrazin-7-ylmethoxy)-benzoicacid methyl ester;

(7S,9aS)-cis-[3-(2-Benzo[d]isoxazol-3-yl-octahydro-pyrido[1,2-a]pyrazin-7-ylmethoxy)-phenyl]-methanol;

(7S,9aS)-cis-4-(2-Benzo[d]isoxazol-3-yl-octahydro-pyrido[1,2-a]-pyrazin-7-ylmethoxy)-benzoicacid methyl ester;

(7S,9aS)-cis-[4-(2-Benzo[d]isoxazol-3-yl-octahydro-pyrido[1,2-a]pyrazin-7-ylmethoxy)-phenyl]-methanol;

(7S,9aS)-cis-2-Benzo[d]isoxazol-3-yl-7-(4-chloromethyl-phenoxymethyl)-octahydropyrido[1,2-a]pyrazine;

(7S,9aS)-cis-2-{1-[2-(Benzo[d]isoxazol-3-yl-methyl-amino)-ethyl-6-methyl-piperidin-3-ylmethoxy}-benzonitrile;

(7S,9aS-{2-[5-(2-Aminomethyl-phenoxymethyl)-2-methyl-piperidin-1-yl]-ethyl}-benzo[d]isoxazol-3-yl-methyl-amine;

(7S,9aS)-cis-4-(2-Benzo[d]isoxazol-3-yl-octahydro-pyrido[1,2-a]pyrazin-7-ylmethoxy)-benzonitrile;

(7S,9aS)-cis-4-(2-Benzo[d]isoxazol-3-yl-octahydro-pyrido-1,2-a]pyrazin-7-ylmethoxy)-benzylamine;

(7S,9aS)-cis-[2-(5-fluoro-benzo[d]isoxazol-3-yl)-octahydro-pyridol[1,2-a]pyrazin-7-yl]-methanol;

(7S,9aS)-cis-2-(5-fluoro-benzo[d]isoxazol-3-yl)-octahydro-pyridol[1,2-a]pyrazine-7-carboxaldehyde;

(7R,9aS)-trans-2-(5-fluoro-benzo[d]isoxazol-3-yl)-octahydro-pyridol[1,2-a]pyrazin-7-carboxaldehyde;

(7R,9aS)-trans-[2-(5-fluoro-benzo[d]isoxazol-3-yl)-octahydro-pyridol[1,2-a]pyrazin-7-yl]-methanoland; and

(7R,9aS)-trans-methanesulfonicacid-2-(5-fluoro-benzo[d]isoxazol-3-yl)-octahydro-pyridol[1,2-a]pyrazin-7-yl-ester.

DETAILED DESCRIPTION OF THE INVENTION

Compounds of the formula I may be prepared according to the followingreaction schemes and discussion. Unless otherwise indicated, W, Z, T, V,R¹, R², R³ and R⁴ and structural formulas I and G in the reactionschemes and discussion that follow are as defined above.

Schemes 1-7 Illustrate Methods of Preparing Compounds of the Formula I.

Scheme 1 illustrates a method of preparing compounds of the formula Ihaving the (7R,9aS)-trans stereochemistry. Referring to Scheme 1, thecompound formula II is combined with the compound of formula III, underMitsunobu coupling conditions, in the presence of triphenylphosphine anda compound of the formula RO₂CN═NCO₂R (IV), wherein R is methyl orethyl, to form the compound of formula V. (See O. Mitsunobu, Synthesis,1 (1981)). Suitable solvents for this reaction include tetrahydrofuran(THF), other ethers and halocarbon solvents, with THF being preferred.This reaction is generally conducted at a temperature from about roomtemperature to about 65° C., for about 1 to about 24 hours. It ispreferably conducted at about 50° C. for about 4 to 18 hours.

Reduction of the compound of formula V yields the compound of formulaVI. This reduction can be accomplished using lithium aluminum hydride asthe reducing agent, in a solvent selected from, diethyl ether and otherdialkyl ethers, preferably diethyl ether, at a temperature from about−5° C. to about room temperature, for about 0.5 to about 18 hours.

The compound of formula VI can then be converted into the compound offormula VII by reacting it with methanesulfonyl chloride, in thepresence of a tertiary amine base such as triethylamine (TEA), inmethylene chloride or another halocarbon solvent, at a temperature fromabout −5° C. to about room temperature, for a period of about 10 minutesto about 2 hours.

Reaction of the resulting compound of formula VII with a compound of theformula HNR¹R², wherein R¹ and R², together with the nitrogen to whichthey are attached, may form a ring, as depicted in Scheme 1, yields thecorresponding compound having formula VIII. Typically, this reaction iscarried out in THF, N,N-dimethylformamide (DMF) or acetonitrile, or amixture of two or more or the foregoing solvents, at a temperature fromabout room temperature to about 100° C., for a period from 1 to about 18hours. The compound of formula VIII is then deprotected to form thehydrochloric acid addition salt of the corresponding compound of formulaIX. This can be accomplished using anhydrous hydrochloric acid (HCl) indiethyl ether, another dialkyl ether or a halocarbon solvent at aboutroom temperature. This reaction can also be carried out without asolvent using trifluoroacetic acid, in which case the bitrifluoroaceticacid addition salt is formed. This reaction is generally run from about2 to about 18 hours.

The desired corresponding compound of formula I-a can be formed byreacting the compound of formula IX from the foregoing reaction with theappropriate compound of formula X, wherein R³ and R⁴ are as definedabove in the definition of compounds of the formula I, and1,8-diazabicyclo[5.4.0]-undec-7-ene (DBU). This reaction is typicallyconducted in pyridine, at a temperature from about 50° C. to about 110°C., for a period of about 1 to about 48 hours.

Scheme 2 illustrates an alternate method of making compounds of theformula I-a. Referring to Scheme 2, the starting material of formula IIis deprotected using the conditions and reactants described above forthe preparation of compounds of the formula IX, to form thedihydrochloric acid or ditrifluoroacetic acid addition salt of theresulting compound of formula XI. Reaction of the resulting compound offormula XI, in the presence of an organic base such as DBU, with thecompound of formula XI yields the corresponding compound of formula XII.

The compound of formula XII produced in the foregoing reaction is thenreacted with 3-hydroxybenzoic acid methyl ester (III), in the presenceof triphenylphosphine and a compound of the formula RO₂CN═NCO₂R (IV),wherein R is methyl or ethyl, using the reaction conditions describedabove for the preparation of compounds of the formula V, to form thecorresponding compound of formula XII, which is then reduced, to formthe corresponding compound of formula XIV. The reduction can beaccomplished using lithium aluminum hydride as the reducing agent, in asolvent selected form THF, diethyl ether and other dialkylethers,preferably THF, at a temperature from about −5° C. to about roomtemperature, for about 0.5 to about 18 hours.

The compound of XIV is then converted into the corresponding compound offormula XV in a manner analogous to the conversion of the compound offormula VI into that of formula VII, which is illustrated in Scheme 1and described above. The desired final product of formula I-a can thenbe obtained from the corresponding compound of the formula XV and theappropriate compound of formula HNR¹R², wherein R¹ and R², together withthe nitrogen to which the are attached, may form a ring, as depicted inScheme 2, using the procedures described above for converting thecompound of formula VII into a compound of the formula, VIII.

Scheme 3 illustrates the preparation of compounds of the formula Ihaving the (7S, 9aS)-cis stereochemistry. These compounds are defined inScheme 3 and hereinafter as compounds of the formula I-b. The reactionsillustrated in this scheme are carried out using reagents and conditionsanalogous to those described above in Scheme 1 for converting thecompound of formula II into a compound of the formula I-a.

Scheme 4 illustrates alternate methods of making compounds of theformula I-b. As illustrated in Scheme 4, compounds of the formula I-bwherein the aminomethyl containing sidechain is attached to the phenoxygroup at the 3′ position can be made using a procedure analogous to thatof Scheme 2. The analogous compounds wherein the aminomethyl sidechainis attached to the phenoxy group at the 4′ position proceed through adifferent intermediate. Specifically, such compounds can be prepared byreacting the corresponding compound of the formula XIVA, wherein thehydroxymethyl group is at the 4′ position, with methanesulfonylchloride, under the same reaction conditions described above for theformation of the compound of formula VII in Scheme 1, to form thecorresponding compound having the formula XVA′. This compound can thenbe converted into the corresponding compound having the formula I-b′using a procedure analogous to that described above for the formation ofcompounds of the formula I-a from the corresponding compounds of formulaXV.

Schemes 5 and 5a illustrate a method for preparing compounds of theformula I wherein W is CH₂NR¹R². The series of reactions illustrated inScheme 5 for converting the starting materials of the formula XIIA intothose of the formula XIX is analogous to the transformation of thecompound of formula XIIA into a compound of the formula XIVA in Scheme4, with the exception that in the first step of this series, i.e., thereaction that adds the phenoxy substituent, the substituted phenolicreactant is a cyano substituted phenol rather than a hydroxy substitutedbenzoic acid methyl ester.

The compound of formula XIX can be converted into the desired finalproduct of formula I-c by reacting it with a compound of the formulaX′—R¹—R²—X′, wherein X′is bromo, chloro or methanesulfonate and thedashed line represents the portion of the ring structure of the finalproduct connecting R¹ and R², in the presence of a base such as sodiumcarbonate or an organic base such as DBU, or with compounds of theformulas R¹X′ and R²X′, sequentially. The reaction with X′—R¹—R²—X′ (orthe sequential reactions with R¹X′ and R²X′) is generally carried out ina solvent such as N,N-dimethylformamide (DMF), THF or methylenechloride, at a temperature from about room temperature to about 100° C.,preferably from about 40° C. to about 100° C., for a period of about 1to 48 hours. The reactions depicted in Scheme 5a can be carried out inan analogous fashion to those of Scheme 5.

Scheme 6 refers to an alternate method of preparing compounds of aformula I having the same stereochemistry at positions 7 and 9a ascompounds of the formula I-a, and wherein the aminomethyl sidechain onthe phenoxy group can be attached at any position (i.e., ortha, meta orpara) of that group. These compounds are referred to in Scheme 6 andhereinafter as compounds of the formula I-d. Referring to Scheme 6, thedihydrochloride salt of the appropriate compound of the formula IX isreacted with syn, anti, or a mixture of the syn and anti isomers of acompound of the formula

(i.e., the appropriately substituted benzohydroximinoyl chloride), inthe presence of a base such as DBU, to form the corresponding compoundof formula XX. Suitable solvents for this reaction includechlorohydrocarbons such as chloroform and methylene chloride. Suitablereaction temperatures range from about −78° C. to about 50° C. Thisreaction is preferably conducted at a temperature from about 20° C. toabout 40° C., for a period of about 0.5 to about 24 hours.

The resulting compound of formula XX can then be converted into thedesired final product of formula I-d by reacting it with a strongnucleophilic organic base (e.g., n-butyl lithium) or sodium hydride.This reaction is typically conducted in a solvent such as toluene, DMFor THF, at a temperature from about room temperature to about 110° C.for about 1 to 48 hours. Preferably, the solvent is a mixture of tolueneand THF and the reaction is carried out at a temperature from about 80°C. to about 100° C.

Scheme 7 illustrates an alternate method that can be used to formcompounds of the formula I-a and the analogous compounds wherein theaminomethyl sidechain is attached to the phenoxy group at the ortho,meta or para positions. Such compounds are referred to in Scheme 7 andhereinafter as “compounds of the formula I-d′”. Referring to Scheme 7, acompound of the formula XIIA is oxidized to form the corresponding(7S,9aS)-cis aldehyde of formula XXIA by dissolving it indichloromethane containing an excess of N,N-diisopropylethylamine, (inmolar equivalents, with respect to the substrate of formula (XIIA)), andtreating it with a slurry of pyridine-sulfur trioxide complex indimethylsulfoxide (DMSO) at an initial temperature below 10° C. Thereaction mixture is then stirred at about ambient temperature for about18 hours. The resulting compound of formula XXIA is then epimerized atthe C-7 carbon to form the corresponding (7R,9aS)-trans aldehyde offormula XXI by stirring a methanol solution of the compound of formulaXXIA it with solid potassium carbonate at about ambient temperature forabout 18 hours.

Reduction of the aldehyde of formula XXI yeilds the correspondingalcohol of formula XII. This reduction can be accomplished by treatmentwith sodium borohydride in methanol for about 18 hours at about ambienttemperature.

The compound of formula XII is reacted with methanesulfonyl chloride, inthe presence of a base such as DBU, in methylene chloride, at atemperature from about −5° C. to about room temperature, for about 10minutes to about 2 hours. The resulting compound of formula XXI is thenreacted with sodium phenolate, wherein the phenyl moiety is substitutedwith a group of the formula CH₂NR¹R² wherein R¹ and R², together withthe nitrogen to which they are attached, may form a ring, as describedabove, to form the desired final product of formula I-d′. Examples ofsolvents in which this reaction can be conducted are DMF andN-methylpyrrolidinone (NMP). The preferred solvent is NMP. The reactiontemperature can range from about 20° C. to about 100° C., and ispreferably between about 70° C. and about 100° C. Generally, thereaction is run for a period for about 1 to 24 hours. As illustrated inScheme 7, the resulting compound of formula I-d′ can be converted intothe corresponding dihydrochloride salt using methods well known to thoseof skill in the art. For example, such compound can be treated with 12Nhydrochloric acid in acetone, or with anhydrous hydrochloric acid in amixture of diethyl ether and ethyl acetate or dichloromethane.

All of the above schemes and corresponding discussions with theexception of Schemes 5 and 5a, the moieties represented as —CH₂NR¹R² and

are interchangeable. Also, the same reactions apply to the formation ofcompounds of the formula I wherein W is alkoxy rather than —CH₂NR¹R², inwhich case the reactant —NHR¹R² is replaced by M⁺O⁻—(C₁-C₆)alkyl,wherein M⁺ is a suitable monovalent cation such as a sodium or lithiumcation.

Unless indicated otherwise, the pressure of each of the above reactionsis not critical. Generally, the reactions will be conducted at apressure of about one to about three atmospheres, preferably at ambientpressure (about one atmosphere).

The compounds of the formula I which are basic in nature are capable offorming a wide variety of different salts with various inorganic andorganic acids. Although such salts must be pharmaceutically acceptablefor administration to animals, it is often desirable in practice toinitially isolate a compound of the formula I from the reaction mixtureas a pharmaceutically unacceptable salt and then simply convert thelatter back to the free base compound by treatment with an alkalinereagent, and subsequently convert the free base to a pharmaceuticallyacceptable acid addition salt. The acid addition salts of the basecompounds of this invention are readily prepared by treating the basecompound with a substantially equivalent amount of the chosen mineral ororganic acid in an aqueous solvent medium or in a suitable organicsolvent such as methanol or ethanol. Upon careful evaporation of thesolvent, the desired solid salt is obtained.

The acids which are used to prepare the pharmaceutically acceptable acidaddition salts of the base compounds of this invention are those whichform non-toxic acid addition salts, i.e., salts containingpharmacologically acceptable anions, such as hydrochloride,hydrobromide, hydroiodide, nitrate, sulfate or bisulfate, phosphate oracid phosphate, acetate, lactate, citrate or acid citrate, tartrate orbitartrate, succinate, maleate, fumarate, gluconate, saccharate,benzoate, methanesulfonate and pamoate [,1,1′-methylene-bis-(2-hydroxy-3-naphthoate)]salts.

Compounds of the formula I and their pharmaceutically acceptable salts(hereinafter also referred to, collectively, as “the active compounds”)are useful psychotherapeutics and are potent agonists and/or antagonistsof the serotonin 1A (5-HT1A) and/or serotonin 1D (5-HT1D) receptors. Theactive compounds are useful in the treatment of hypertension,depression, generalized anxiety disorder, phobias (e.g., agoraphobia,social phobia and simple phobias), posttraumatic stress syndrome,avoidant personality disorder, sexual dysfunction (e.g., prematureejaculation), eating disorders (e.g., anorexia nervosa and bulimianervosa), obesity, chemical dependencies (e.g., addictions to alcohol,cocaine, heroin, phenobarbital, nicotine and benzodiazepines), clusterheadache, migraine, pain, Alzheimer's disease, obsessive-compulsivedisorder, panic disorder, memory disorders (e.g., dementia, amnesticdisorders, and age-related cognitive decline (ARCD)), Parkinson'sdiseases (e.g., dementia in Parkinson's disease, neuroleptic-inducedparkinsonism and tardive dyskinesias), endocrine disorders (e.g.,hyperprolactinaemia), vasospasm (particularly in the cerebralvasculature), cerebellar ataxia, gastrointestinal tract disorders(involving changes in motility and secretion), negative symptoms ofschizophrenia, premenstrual syndrome, fibromyalgia syndrome, stressincontinence, Tourette's syndrome, trichotillomania, kleptomania, maleimpotence, cancer (e.g., small cell lung carcinoma), chronic paroxysmalhemicrania and headache (associated with vascular disorders).

The affinities of the compounds of this invention for the variousserotonin-1 receptors can be determined using standard radioligandbinding assays as described in the literature. The 5-HT1A affinity canbe measured using the procedure of Hoyer et al. (Brain Res., 376, 85(1986)). The 5-HT1D affinity can be measured using the procedure ofHeuring and Peroutka (J. Neurosci., 7, 894 (1987)).

The in vitro activity of the compounds of the present invention at the5-HT1D binding site may be determined according to the followingprocedure. Bovine caudate tissue is homogenized and suspended in 20volumes of a buffer containing 50 mM TRIS.hydrochloride(tris[hydroxymethyl]aminomethane hydrochloride) at a pH of 7.7. Thehomogenate is then centrifuged at 45,000G for 10 minutes. Thesupernatant is then discarded and the resulting pellet resuspended inapproximately 20 volumes of 50 mM TRIS.hydrochloride buffer at pH 7.7.This suspension is then pre-incubated for 15 minutes at 37° C., afterwhich the suspension is centrifuged again at 45,000G for 10 minutes andthe supernatant discarded. The resulting pellet (approximately 1 gram)is resuspended in 150 ml of a buffer of 15 mM TRIS.hydrochloridecontaining 0.01 percent ascorbic acid with a final pH of 7.7 and alsocontaining 10 mM pargyline and 4 mM calcium chloride (CaCl₂). Thesuspension is kept on ice at least 30 minutes prior to use.

The inhibitor, control or vehicle is then incubated according to thefollowing procedure. To 50 ml of a 20 percent dimethylsulfoxide(DMSO)/80 percent distilled water solution is added 200 ml of tritiated5-hydroxytryptamine (2 nM) in a buffer of 50 mM TRIS.hydrochloridecontaining 0.01 percent ascorbic acid at pH 7.7 and also containing 10mM pargyline and 4 mM calcium chloride, plus 100 nM of 8-hydroxy-DPAT(dipropylaminotetraline) and 100 nM of mesulergine. To this mixture isadded 750 ml of bovine caudate tissue, and the resulting suspension isvortexed to ensure a homogenous suspension. The suspension is thenincubated in a shaking water bath for 30 minutes at 25° C. Afterincubation is complete, the suspension is filtered using glass fiberfilters (e.g., Whatman GF/B-filters). The pellet is then washed threetimes with 4 ml of a buffer of 50 mM TRIS.hydrochloride at pH 7.7. Thepellet is then placed in a scintillation vial with 5 ml of scintillationfluid (aquasol 2) and allowed to sit overnight. The percent inhibitioncan be calculated for each dose of the compound. An IC₅₀ value can thenbe calculated from the percent inhibition values.

The activity of the compounds of the present invention for 5-HT1Abinding ability can be determined according to the following procedure.Rat brain cortex tissue is homogenized and divided into samples of 1gram lots and diluted with 10 volumes of 0.32 M sucrose solution. Thesuspension is then centrifuged at 900G for 10 minutes and the supernateseparated and recentrifuged at 70,000G for 15 minutes. The supernate isdiscarded and the pellet re-suspended in 10 volumes of 15 mMTRIS.hydrochloride at pH 7.5. The suspension is allowed to incubate for15 minutes at 37° C. After pre-incubation is complete, the suspension iscentrifuged at 70,000G for 15 minutes and the supernate discarded. Theresulting tissue pellet is resuspended in a buffer of 50 mMTRIS.hydrochloride at pH 7.7 containing 4 mM of calcium chloride and0.01 percent ascorbic acid. The tissue is stored at −70° C. until readyfor an experiment. The tissue can be thawed immediately prior to use,diluted with 10 mm pargyline and kept on ice.

The tissue is then incubated according to the following procedure. Fiftymicroliters of control, inhibitor, or vehicle (1 percent DMSO finalconcentration) is prepared at various dosages. To this solution is added200 ml of tritiated DPAT at a concentration of 1.5 nM in a buffer of 50mM TRIS.hydrochloride at pH 7.7 containing 4 mM calcium chloride, 0.01percent ascorbic acid and pargyline. To this solution is then added 750ml of tissue and the resulting suspension is vortexed to ensurehomogeneity. The suspension is then incubated in a shaking water bathfor 30 minutes at 37° C. The solution is then filtered, washed twicewith 4 ml of 10 mM TRIS.hydrochloride at pH 7.5 containing 154 mM ofsodium chloride. The percent inhibition is calculated for each dose ofthe compound, control or vehicle. IC₅₀ values are calculated from thepercent inhibition values.

The compounds of formula I of the present invention described in thefollowing Examples were assayed for 5-HT1A and 5-HT1D affinity using theaforementioned procedures. All such compounds of the invention that weretested exhibited IC₅₀'s less than 0.60 mM for 5-HT1D affinity and IC₅₀'sless than 1.0 mM for 5-HT1A affinity.

The agonist and antagonist activities of the compounds of the inventionat 5-HT1A and 5-HT1D receptors can be determined using a singlesaturating concentration according to the following procedure. MaleHartley guinea pigs are decapitated and 5-HT1A receptors are dissectedout of the hippocampus, while 5-HT1D receptors are obtained by slicingat 350 mM on a Mcllwain tissue chopper and dissecting out the substantianigra from the appropriate slices. The individual tissues arehomogenized in 5 mM HEPES buffer containing 1 mM EGTA (pH 7.5) using ahand-held glass-Teflon® homogenizer and centrifuged at 35,000×g for 10minutes at 4° C. The pellets are resuspended in 100 mM HEPES buffercontaining 1 mM EGTA (pH 7.5) to a final protein concentration of 20 mg(hippocampus) or 5 mg (substantia nigra) of protein per tube. Thefollowing agents are added so that the reaction mix in each tubecontained 2.0 mM MgCl₂, 0.5 mM ATP, 1.0 mM cAMP, 0.5 mM IBMX, 10 mMphosphocreatine, 0.31 mg/mL creatine phosphokinase, 100 mM GTP and 0.5-1microcuries of [32P]-ATP (30 Ci/mmol: NEG-003—New England Nuclear).Incubation is initiated by the addition of tissue to siliconizedmicrofuge tubes (in triplicate) at 30° C. for 15 minutes. Each tubereceives 20 mL tissue, 10 mL drug or buffer (at 10×final concentration),10 mL 32 nM agonist or buffer (at 10× final concentration), 20 mLforskolin (3 mM final concentration) and 40 mL of the preceding reactionmix. Incubation is terminated by the addition of 100 mL 2% SDS, 1.3 mMcAMP, 45 mM ATP solution containing 40,000 dpm [³H]-cAMP (30 Ci/mmol:NET-275—New England Nuclear) to monitor the recovery of cAMP from thecolumns. The separation of [³²P]-ATP and [³²P]-cAMP is accomplishedusing the method of Salomon et al., Analytical Biochemistry, 1974, 58,541-548. Radioactivity is quantified by liquid scintillation counting.Maximal inhibition is defined by 10 mM (R)-8-OH-DPAT for 5-HT1Areceptors, and 320 nM 5-HT for 5-HT1D receptors. Percent inhibitions bythe test compounds are then calculated in relation to the inhibitoryeffect of (R)-8-OH-DPAT for 5-HT1A receptors or 5-HT for 5-HT1Dreceptors. The reversal of agonist induced inhibition offorskolin-stimulated adenylate cyclase activity is calculated inrelation to the 32 nM agonist effect.

The compounds of the invention can be tested for in vivo activity forantagonism of 5-HT1D agonist-induced hypothermia in guinea pigsaccording to the following procedure.

Male Hartley guinea pigs from Charles River, weighing 250-275 grams onarrival and 300-600 grams at testing, serve as subjects in theexperiment. The guinea pigs are housed under standard laboratoryconditions on a 7 a.m. to 7 p.m. lighting schedule for at least sevendays prior to experimentation. Food and water are available ad libitumuntil the time of testing.

The compounds of the invention can be administered as solutions in avolume of 1 ml/kg. The vehicle used is varied depending on compoundsolubility. Test compounds are typically administered either sixtyminutes orally (p.o.) or 0 minutes subcutaneously (s.c.) prior to a5-HT1D agonist, such as[3-(1-methylpyrrolidin-2-ylmethyl)-1H-indol-5-yl]-(3-nitropyridin-3-yl)-amine,which can be prepared as described in PCT publication WO93/111 06,published Jun. 10, 1993 which is administered at a dose of 5.6 mg/kg,s.c. Before a first temperature reading is taken, each guinea pig isplaced in a clear plastic shoe box containing wood chips and a metalgrid floor and allowed to acclimate to the surroundings for 30 minutes.Animals are then returned to the same shoe box after each temperaturereading. Prior to each temperature measurement each animal is firmlyheld with one hand for a 30-second period. A digital thermometer with asmall animal probe is used for temperature measurements. The probe ismade of semi-flexible nylon with an epoxy tip. The temperature probe isinserted 6 cm. into the rectum and held there for 30 seconds or until astable recording is obtained. Temperatures are then recorded.

In p.o. screening experiments, a “pre-drug” baseline temperature readingis made at −90 minutes, the test compound is given at −60 minutes and anadditional −30 minute reading is taken. The 5-HT1D agonist is thenadministered at 0 minutes and temperatures are taken 30, 60, 120 and 240minutes later.

In subcutaneous screening experiments, a pre-drug baseline temperaturereading is made at −30 minutes. The test compound and 5-HT1D agonistsare given concurrently and temperatures are taken at 30, 60, 120 and 240minutes later.

Data are analyzed with two-way analysis of variants with repeatedmeasures in Newman-Keuls post hoc analysis.

The active compounds of the invention can be evaluated as anti-migraineagents by testing the extent to which they mimic sumatriptan incontracting the dog isolated saphenous vein strip [P. P. A. Humphrey etal., Br. J. Pharmacol., 94, 1128 (1988)]. This effect can be blocked bymethiothepin, a known serotonin antagonist. Sumatriptan is known to beuseful in the treatment of migraine and produces a selective increase incarotid vascular resistance in the anesthetized dog. The pharmacologicalbasis of sumatriptan efficacy has been discussed in W. Fenwick et al.,Br. J. Pharmacol., 96, 83 (1989).

The serotonin 5-HT1 agonist activity can be determined by the in vitroreceptor binding assays, as described for the 5-HT1A receptor using ratcortex as the receptor source and [³H]-8-OH-DPAT as the radioligand [D.Hoyer et al. Eur. J. Pharm., 118, 13 (1985)] and as described for the5-HT1D receptor using bovine caudate as the receptor source and[3H]serotonin as the radioligand [R. E. Heuring and S. J. Peroutka, J.Neuroscience, 7, 894 (1987)]. Of the active compounds tested, allexhibited an IC₅₀ in either assay of 1 mM or less.

The compounds of formula I may advantageously be used in conjunctionwith one or more other therapeutic agents, for instance, differentantidepressant agents such as tricyclic antidepressants (e.g.,amitriptyline, dothiepin, doxepin, trimipramine, butripyline,clomipramine, desipramine, imipramine, iprindole, lofepramine,nortriptyline or protriptyline), monoamine oxidase inhibitors (e.g.,isocarboxazid, phenelzine or tranylcyclopramine) or 5-HT re-uptakeinhibitors (e.g., fluvoxamine, sertraline, fluoxetine or paroxetine),and/or with antiparkinsonian agents such as dopaminergicantiparkinsonian agents (e.g., levodopa, preferably in combination witha peripheral decarboxylase inhibitor e.g., benserazide or carbidopa, orwith a dopamine agonist e.g., bromocriptine, lysuride or pergolide). Itis to be understood that the present invention covers the use of acompound of general formula (i) or a physiologically acceptable salt orsolvate thereof in combination with one or more other therapeuticagents.

Compounds of the formula I and the pharmaceutically acceptable saltsthereof, in combination with a 5-HT re-uptake inhibitor (e.g.,fluvoxamine, sertraline, fluoxetine or paroxetine), preferablysertraline, or a pharmaceutically acceptable salt or polymorph thereof(the combination of a compound of formula I with a 5-HT re-uptakeinhibitor is referred herein to as “the active combination”), are usefulpsychotherapeutics and may be used in the treatment or prevention ofdisorders the treatment or prevention of which is facilitated bymodulating serotonergic neurotransmission such as hypertension,depression (e.g., depression in cancer patients, depression inParkinson's patients, postmyocardial infarction depression, subsyndromalsymptomatic depression, depression in infertile women, pediatricdepression, major depression, single episode depression, recurrentdepression, child abuse induced depression, and post partum depression),generalized anxiety disorder, phobias (e.g., agoraphobia, social phobiaand simple phobias), posttraumatic stress syndrome, avoidant personalitydisorder, premature ejaculation, eating disorders (e.g., anorexianervosa and bulimia nervosa), obesity, chemical dependencies (e.g.,addictions to alcohol, cocaine, heroin, phenobarbital, nicotine andbenzodiazepines), cluster headache, migraine, pain, Alzheimer's disease,obsessive-compulsive disorder, panic disorder, memory disorders (e.g.,dementia, amnestic disorders, and age-related cognitive decline (ARCD)),Parkinson's diseases (e.g., dementia in Parkinson's disease,neuroleptic-induced parkinsonism and tardive dyskinesias), endocrinedisorders (e.g., hyperprolactinaemia), vasospasm (particularly in thecerebral vasculature), cerebellar ataxia, gastrointestinal tractdisorders (involving changes in motility and secretion), negativesymptoms of schizophrenia, premenstrual syndrome, fibromyalgia syndrome,stress incontinence, Tourette's syndrome, trichotillomania, kleptomania,male impotence, cancer (e.g., small cell lung carcinoma), chronicparoxysmal hemicrania and headache (associated with vascular disorders).

Serotonin (5-HT) re-uptake inhibitors, preferably sertraline, exhibitpositive activity against depression; chemical dependencies; anxietydisorders including panic disorder, generalized anxiety disorder,agoraphobia, simple phobias, social phobia, and post-traumatic stressdisorder; obsessive-compulsive disorder; avoidant personality disorderand premature ejaculation in mammals, including humans, due in part totheir ability to block the synaptosomal uptake of serotonin.

U.S. Pat. No. 4,536,518 describes the synthesis, pharmaceuticalcomposition and use of sertraline for depression and is herebyincorporated by reference in its entirety.

Activity of the active combination as antidepressants and relatedpharmacological properties can be determined by methods (1)-(4) below,which are described in Koe, B. et al., Journal of Pharmacology andExperimental Therapeutics, 226 (3), 686-700 (1983). Specifically,activity can be determined by studying (1) their ability to affect theefforts of mice to escape from a swim-tank (Porsolt mouse “behaviordespair” test), (2) their ability to potentiate5-hydroxytryptophan-induced behavioral symptoms in mice in vivo, (3)their ability to antagonize the serotonin-depleting activity ofp-chloroamphetamine hydrochloride in rat brain in vivo, and (4) theirability to block the uptake of serotonin, norepinephrine and dopamine bysynaptosomal rat brain cells in vitro. The ability of the activecombination to counteract reserpine hypothermia in mice in vivo can bedetermined according to the methods described in U.S. Pat. No.4,029,731.

The compositions of the present invention may be formulated in aconventional manner using one or more pharmaceutically acceptablecarriers. Thus, the active compounds of the invention may be formulatedfor oral, buccal, intranasal, parenteral (e.g., intravenous,intramuscular or subcutaneous) or rectal administration or in a formsuitable for administration by inhalation or insufflation.

For oral administration, the pharmaceutical compositions may take theform of, for example, tablets or capsules prepared by conventional meanswith pharmaceutically acceptable excipients such as binding agents(e.g., pregelatinized maize starch, polyvinylpyrrolidone orhydroxypropyl methylcellulose); fillers (e.g., lactose, microcrystallinecellulose or calcium phosphate); lubricants (e.g., magnesium stearate,talc or silica); disintegrants (e.g., potato starch or sodium starchglycolate); or wetting agents (e.g., sodium lauryl sulphate). Thetablets may be coated by methods well known in the art. Liquidpreparations for oral administration may take the form of, for example,solutions, syrups or suspensions, or they may be presented as a dryproduct for constitution with water or other suitable vehicle beforeuse. Such liquid preparations may be prepared by conventional means withpharmaceutically acceptable additives such as suspending agents (e.g.,sorbitol syrup, methyl cellulose or hydrogenated edible fats);emulsifying agents (e.g., lecithin or acacia); non-aqueous vehicles(e.g., almond oil, oily esters or ethyl alcohol); and preservatives(e.g., methyl or propyl p-hydroxybenzoates or sorbic acid).

For buccal administration, the composition may take the form of tabletsor lozenges formulated in conventional manner.

The active compounds of the invention may be formulated for parenteraladministration by injection, including using conventionalcatheterization techniques or infusion. Formulations for injection maybe presented in unit dosage form, e.g., in ampules or in multi-dosecontainers, with an added preservative. The compositions may take suchforms as suspensions, solutions or emulsions in oily or aqueousvehicles, and may contain formulating agents such as suspending,stabilizing and/or dispersing agents. Alternatively, the activeingredient may be in powder form for reconstitution with a suitablevehicle, e.g., sterile pyrogen-free water, before use.

The active compounds of the invention may also be formulated in rectalcompositions such as suppositories or retention enemas, e.g., containingconventional suppository bases such as cocoa butter or other glycerides.

For intranasal administration or administration by inhalation, theactive compounds of the invention are conveniently delivered in the formof a solution or suspension from a pump spray container that is squeezedor pumped by the patient or as an aerosol spray presentation from apressurized container or a nebulizer, with the use of a suitablepropellant, e.g., dichlorodifluoromethane, trichlorofluoromethane,dichlorotetrafluoroethane, carbon dioxide or other suitable gas. In thecase of a pressurized aerosol, the dosage unit may be determined byproviding a valve to deliver a metered amount. The pressurized containeror nebulizer may contain a solution or suspension of the activecompound. Capsules and cartridges (made, for example, from gelatin) foruse in an inhaler or insufflator may be formulated containing a powdermix of a compound of the invention and a suitable powder base such aslactose or starch.

A proposed dose of the active compounds of the invention for oral,parenteral or buccal administration to the average adult human for thetreatment of the conditions referred to above (e.g., depression) is 0.1to 200 mg of the active ingredient per unit dose which could beadministered, for example, 1 to 4 times per day.

Aerosol formulations for treatment of the conditions referred to above(e.g., migraine) in the average adult human are preferably arranged sothat each metered dose or “puff” of aerosol contains 20 mg to 1000 mg ofthe compound of the invention. The overall daily dose with an aerosolwill be within the range 100 mg to 10 mg. Administration may be severaltimes daily, for example 2, 3, 4 or 8 times, giving for example, 1, 2 or3 doses each time.

In connection with the use of an active compound of this invention witha 5-HT re-uptake inhibitor, preferably sertraline, for the treatment ofsubjects possessing any of the above conditions, it is to be noted thatthese compounds may be administered either alone or in combination withpharmaceutically acceptable carriers by either of the routes previouslyindicated, and that such administration can be carried out in bothsingle and multiple dosages. More particularly, the active combinationcan be administered in a wide variety of different dosage forms, i.e.,they may be combined with various pharmaceutically-acceptable inertcarriers in the form of tablets, capsules, lozenges, troches, hardcandies, powders, sprays, aqueous suspension, injectable solutions,elixirs, syrups, and the like. Such carriers include solid diluents orfillers, sterile aqueous media and various non-toxic organic solvents,etc. Moreover, such oral pharmaceutical formulations can be suitablysweetened and/or flavored by means of various agents of the typecommonly employed for such purposes. In general, the compounds offormula I are present in such dosage forms at concentration levelsranging from about 0.5% to about 90% by weight of the total composition,i.e., in amounts which are sufficient to provide the desired unit dosageand a 5-HT re-uptake inhibitor, preferably sertraline, is present insuch dosage forms at concentration levels ranging from about 0.5% toabout 90% by weight of the total composition, i.e., in amounts which aresufficient to provide the desired unit dosage.

A proposed daily dose of an active compound of this invention in thecombination formulation (a formulation containing an active compound ofthis invention and a 5-HT re-uptake inhibitor) for oral, parenteral,rectal or buccal administration to the average adult human for thetreatment of the conditions referred to above is from about 0.01 mg toabout 2000 mg, preferably from about 0.1 mg to about 200 mg of theactive ingredient of formula I per unit dose which could beadministered, for example, 1 to 4 times per day.

A proposed daily dose of a 5-HT re-uptake inhibitor, preferablysertraline, in the combination formulation for oral, parenteral orbuccal administration to the average adult human for the treatment ofthe conditions referred to above is from about 0.1 mg to about 2000 mg,preferably from about 1 mg to about 200 mg of the 5-HT re-uptakeinhibitor per unit dose which could be administered, for example, 1 to 4times per day.

A preferred dose ratio of sertraline to an active compound of thisinvention in the combination formulation for oral, parenteral or buccaladministration to the average adult human for the treatment of theconditions referred to above is from about 0.00005 to about 20,000,preferably from about 0.25 to about 2,000.

Aerosol combination formulations for treatment of the conditionsreferred to above in the average adult human are preferably arranged sothat each metered dose or “puff” of aerosol contains from about 0.01 mgto about 100 mg of the active compound of this invention, preferablyfrom about 1 mg to about 10 mg of such compound. Administration may beseveral times daily, for example 2, 3, 4 or 8 times, giving for example,1, 2 or 3 doses each time.

Aerosol formulations for treatment of the conditions referred to abovein the average adult human are preferably arranged so that each metereddose or “puff” of aerosol contains from about 0.01 mg to about 2000 mgof a 5-HT re-uptake inhibitor, preferably sertraline, preferably fromabout 1 mg to about 200 mg of sertraline. Administration may be severaltimes daily, for example 2, 3, 4 or 8 times, giving for example, 1, 2 or3 doses each time.

As previously indicated, a 5-HT re-uptake inhibitor, preferablysertraline, in combination with compounds of formula I are readilyadapted to therapeutic use as antidepressant agents. In general, theseantidepressant compositions containing a 5-HT re-uptake inhibitor,preferably sertraline, and a compound of formula I are normallyadministered in dosages ranging from about 0.01 mg to about 100 mg perkg of body weight per day of a 5-HT re-uptake inhibitor, preferablysertraline, preferably from about 0.1 mg to about 10 mg per kg of bodyweight per day of sertraline; with from about 0.001 mg. to about 100 mgper kg of body weight per day of a compound of formula 1, preferablyfrom about 0.01 mg to about 10 mg per kg of body weight per day of acompound of formula 1, although variations will necessarily occurdepending upon the conditions of the subject being treated and theparticular route of administration chosen.

The following Examples illustrate the preparation of the compounds ofthe present invention. Melting points are uncorrected. NMR data arereported in parts per million and are referenced to the deuterium locksignal from the sample solvent (deuteriochloroform unless otherwisespecified). Specific rotations were measured at room temperature usingthe sodium D line (589 nm). Commercial reagents were utilized withoutfurther purification. THF refers to tetrahydrofuran. DMF refers toN,N-dimethylformamide. Chromatography refers to column chromatographyperformed using 47-61 mesh silica gel and executed under nitrogenpressure (flash chromatography) conditions. Room or ambient temperaturerefers to 20-25° C. All non-aqueous reactions were run under a nitrogenatmosphere for convenience and to maximize yields. Concentration atreduced pressure means that a rotary evaporator was used.

EXAMPLE 1(7S,9aS)-CIS-1-(3-{1-[2-(BENZO[d]ISOXASOL-3-YL-METHYL-AMINO)-ETHYL]-6-METHYL-PIPERIDIN-3-YLMETHOXY}-BENZYL)-AZETIDIN-3-OL(DIASTEREOMERS)

Step 1

(7S,9aS)-cis-7-(3-methoxycarbonyl-phenoxymethyl)-octahydro-pyrido[1,2-a]pyrazine-2-carboxylicacid tert-butyl ester

Utilizing(7R,9aS)-cis-7-(hydroxymethyl)-2-(tert-butoxycarbonyl)-2,3,4,6,7,8,9,9a-octahydro-1H-pyrido[1,2-a]pyrazine(European Patent Application EP 646116, published Apr. 5, 1995; 8.14, 30mmol) in place of the corresponding (7R,9aS)-trans isomer as a reactantin the procedure of Example 5, Step 1 (with appropriate scaling of otherreactants/solvents), the title compound was prepared as a colorless oil(8.80 g, 73% yield; flash chromatography: silica gel, 47-61 micron mesh;elution with ethyl acetate/hexane=2:8 in volume).

MS m/z 405 (M+1).

Step 2

(7S,9aS)-cis-{2-[5-(3-hydroxymethyl-phenoxymethyl)-2-methyl-piperidin-1-yl]ethyl}-methyl-carbamicacid tert-butyl ester

Utilizing the general procedure described in Example 5, Step 2 andsubstituting the product of the previous step for the corresponding(7R,9aS)-trans isomer as a reactant (8.80 g, 21.8 mmol) and appropriatescaling of other reactants/solvents, the title compound was prepared(7.39 g, 90% yield) as a colorless oil.

MS m/z 377 (M+1).

Step 3

(7S,9aS)-cis-(2-{5-[3-(3-hydroxy-azetidin-1-yl-methyl)-phenoxymethyl]-2-methyl-piperidin-1-yl}-ethyl)-methyl-carbamicacid tert-butyl ester (diastereomers)

Utilizing the general procedure Example 5, Step 3, and substituting asreactants the title compound of the previous step (307 mg, 0.82 mmol)for the corresponding (7R,9aS)-trans isomer and(R,S)-3-hydroxy-azetidine (175 mg, 2.4 mmol), with appropriate scalingof other reagents/solvents, the title compound was prepared as acolorless oil (224 mg, 63% yield; flash chromatography: silica gel,47-61 micron mesh; elution with methanol/methylene chloride=8:92 involume).

¹³C NMR (75 MHz, CDCl₃) δ 159.6, 154.8, 139.0, 129.3, 120.7, 114.6,113.7, 79.6, 68.7, 64.1, 63.5, 62.8, 61.0, 56.5, 54.8, 33.7, 28.4, 25.0,24.7 ppm. MS m/z 432 (M+1).

Step 4

(7S,9aS)-cis-1-{3-[6-methyl-1-(2-methylamino-ethyl)-piperidin-3-ylmethoxy]-benzyl}-azetidin-3-ol dihydrochloride (diastereomers)

Utilizing the general procedure of Example 5, Step 4, and substitutingas a reactant the title compound of the previous step (224 mg, 0.52mmol) for the corresponding (7R,9aS)-trans isomer, with appropriatescaling of other reactants/solvents the title compound was prepared(dihydrochloride salt) as a colorless viscous oil (100 mg, 48% yield).

Step 5

(7S,9aS)-cis-1-(3-{1-[2-(benzo[d]isoxazol-3-yl-methyl-amino)-ethyl]-6-methyl-piperidin-3-ylmethoxy}-benzyl)-azetidin-3-ol(diastereomers)

Utilizing the general procedure of Example 5, Step 5, and substitutingthe title compound from the previous step (100 mg, 0.25 mmol) for thecorresponding (7R,9aS)-trans isomer as a reactant, with proper scalingof other reactants/solvents, the title compound was prepared in freebase form (39 mg, 35% yield) as a colorless oil (flash chromatography:silica gel, 47-61 micron mesh; elution with methanol/methylenechloride=8:92 in volume). ¹³C NMR (75 MHz, CDCl₃) δ 164.0, 161.2, 159.4,139.4, 129.5, 129.4, 122.2, 120.7, 116.3, 114.6, 113.6, 110.5, 68.7,64.1, 63.6, 62.7, 60.4, 56.5, 54.2, 53.7, 48.3, 33.7, 25.1, 24.8 ppm.

MS m/z 449 (M+1).

The dihydrochloride was readily prepared from the free base in amorphousform using the general procedure of Example 5, Step 5.

EXAMPLE 2(7R,9aS)-CIS-[3-(2-BENZO[d]ISOXAZOL-3-YL-OCTAHYDRO-PYRIDO[1,2-a]PYRAZIN-7-YLMETHOXY)-BENZYL]-CYCLOPROPYL-AMINE

Step 1

(7S,9aS)-cis-7-(3-Cyclopropylaminomethyl-phenoxymethyl)-octahydro-pyrido[1,2-a]pyrazine-2-carboxylic acid tert-butyl ester

Utilizing the title compound of Example 1/Step 2 (750 mg, 2.0 mmol) andcyclopropylamine (414 μL, 6.0 mmol) as reactants; and the generalprocedure of Example 1/Step 3, with appropriate scaling of otherreagents/solvents, the title compound was prepared as a colorless oil(431 mg, 52% yield; flash chromatography: silica gel, 47-61 micron mesh;elution with methanol/methylene chloride=4:96 in volume).

MS m/z 416 (M+1).

Step 2

(7S,9aS)-cis-Cyclopropyl-[3-(octahydro-pyrido[1,2-a]pyrazin-7-ylmethoxy)-benzyl]-aminedihydrochloride

Utilizing the title compound from the previous step (431 mg, 1.0 mmol)and the appropriately scaled reactant/solvents and general procedure ofExample 1/Step 4, the title compound was prepared and isolated(dihydrochloride salt) as a colorless amorphous solid (357 mg, 88%yield).

MS m/z 316 (M+1).

Step 3

(7S,9aS)-cis-[3-(2-Benzo[d]isoxazol-3-yl-octahydro-pyrido[1,2-a]pyrazin-7-ylmethoxy)-benzyl]-cyclopropyl-amine

Utilizing the title compound from the previous step (200 mg, 0.52 mmol),3-chloro-benzo[d]isoxazole (98 mg, 0.64 mmol), and1,8-diazabicyclo[5.4.0]-undec-7-ene (256 μl, 1.69 mmol) as reactants,pyridine (250 μl) as solvent, and the general procedure of Example 1(with proper scaling of reactants/solvents), the title compound wasprepared in free base form (60 mg, 27% yield) as a colorless oil (flashchromatography: silica, 47-61 micron mesh; elution withmethanol/methylene chloride=4:96 in volume). The title compound productwas identical in all respects to the title compound product of Example19.

EXAMPLE 3(7S,9aS)-CIS-2-BENZO[d]ISOXAZOL-3-YL-7-[3-(2-METHOXYMETHYL-PYRROLIDIN-1-YLMETHYL)-PHENOXYMETHYL-OCTAHYDRO-PYRIDO[1.2-a]PYRAZINE

Step 1

(7S,9aS)-cis-7-[3-(2-Methoxymethyl-pyrrolidin-1-ylmethyl)-phenoxymethyl]-octahydro-pyrido[1,2-a]pyrazine-2-carboxylicacid tert-butyl ester

Utilizing the title compound of Example 1/Step 2 (750 mg, 2 mmol) and2S-methoxymethyl-pyrrolidine (Aldrich Chemical Co.; 740 μl, 6 mmol) asreactants; and the general procedure of Example 1/Step 3, withappropriate scaling of other reagents/solvents, the title compound wasprepared as a colorless oil (449 mg, 47% yield; flash chromatography:silica gel, 47-61 micron mesh; elution with methanol/methylenechloride=6:94 in volume).

MS m/z 474 (M+1); ¹³C NMR (100 MHz, CDCl₃) δ 159.1, 154.5, 141.2, 128.9,121.1, 115.2, 112.7, 79.4, 76.4, 68.5, 62.9, 60.9, 59.6, 59.0, 56.4,54.7, 54.6, 33.6, 28.4, 28.3, 24.9, 24.6, 22.7

Step 2

(7S,9aS)-cis-7-[3-(2-Methoxymethyl-pyrrolidin-1-ylmethyl)-phenoxymethyl]-octahydro-pyrido[1,2-a]pyrazinedihydrochloride

Utilizing the title compound from the previous step (449 mg, 0.95 mmol)and the appropriately scaled reactant/solvents and general procedure ofExample 1/Step 4, the title compound was prepared and isolated(dihydrochloride salt) as a colorless amorphous solid (428 mg,quantitative yield).

MS m/z 373 (M+1).

Step 3

(7S,9aS)-cis-Benzo[d]isoxazol-3-yl-7-[3-(2-methoxymethyl-pyrrolidin-1-ylmethyl)-phenoxymethyl]-octahydro-pyrido[1,2-a]pyrazine

Utilizing the title compound from the previous step (250 mg, 0.56 mmol),3-chloro-benzo[d]isoxazole (106 mg, 0.69 mmol), and1,8-diazabicyclo[5.4.0]-undec-7-ene (273 μl, 1.8 mmol) as reactants,pyridine (260 μl) as solvent, and the general procedure of Example 1(with proper scaling of reactants/solvents), the title compound wasprepared in free base form (107 mg, 37% yield) as a colorless oil (flashchromatography: silica, 47-61 micron mesh; elution withmethanol/methylene chloride=5:95 in volume). The title compound productwas identical in all respects to the title compound product of Example18.

EXAMPLE 4(7S,9aS)-CIS-2-BENZO[d]ISOXAZOL-3-YL-7-[3-(4-ETHYL-PIPERAZIN-1-YLMETHYL-PHENOXYMETHYL]-OCTAHYDRO-PYRIDO[1,2-a]PYRAZINE

Step 1

(7S,9aS)-cis-7-[3-(4-Ethyl-piperazin-1-ylmethyl)-phenoxymethyl]-octahydro-pyrido[1.2-a]pyrazine-2-carboxylicacid tert-butyl ester

Utilizing the title compound of Example 1/Step 2 (750 mg, 2.0 mmol) andN-ethyl piperazine (762 μl, 6.0 mmol) as reactants; and the generalprocedure of Example 1/Step 3, with appropriate scaling of otherreagents/solvents, the title compound was prepared as a colorless oil(430 mg, 46% yield; flash chromatography: silica gel, 47-61 micron mesh;elution with methanol/methylene chloride=8:92 in volume).

MS m/z 473 (M+1); ¹³C NMR (100 MHz, CDCl₃) δ 163.0, 136.3, 133.9, 126.1,120.3, 119.4, 82.0, 70.9, 69.4, 63.6, 58.0, 55.5, 54.1, 48.3, 44.1,37.3, 36.0, 33.7, 26.0, 25.6, 18.0, 6.8.

Step 2

(7S,9aS)-cis-7-[3-(4-Ethyl-piperazin-1-ylmethyl)-phenoxymethyl]-octahydro-pyrido[1,2-a]pyrazinedihydrochloride

Utilizing the title compound from the previous step (410 mg, 0.87 mmol)and the appropriately scaled reactant/solvents and general procedure ofExample 1/Step 4, the title compound was prepared and isolated(dihydrochloride salt) as a colorless amorphous solid (quantitativeyield).

MS m/z 373 (M+1).

Step 3

(7S,9aS)-cis-Benzo[d]isoxazol-3-yl-7-[3-(4-ethyl-piperazin-1-ylmethyl)-phenoxymethyl]-octahydro-pyrido[1,2-a]pyrazine

Utilizing the title compound from the previous step (250 mg, 0.56 mmol),3-chloro-benzo[d]isoxazole (106 mg, 0.69 mmol), and1,8-diazabicyclo[5.4.0]-undec-7-ene (275 μl, 1.8 mmol) as reactants,pyridine (260 μl) as solvent, and the general procedure of Example 1(with proper scaling of reactants/solvents), the title compound wasprepared in free base form (184 mg, 67% yield) as a colorless oil (flashchromatography: silica, 47-61 micron mesh; elution withmethanol/methylene chloride=5:95 in volume). The title compound productwas identical in all respects to the title compound product of Example21.

EXAMPLE 5(7R,9aS)-TRANS-2-(5-FLUORO-BENZO[d]ISOXAZOL-3-YL)-7-(3-PYRROLIDIN-1-YLMETHYL-PHENOXYMETHYL)-OCTAHYDRO-PYRIDO[1,2-a]PYRAZINE

Step 1

(7R,9aS)-trans-7-(3-methoxycarbonylphenoxymethyl)-octahydro-pyrido-1,2-a]pyrazine-2-carboxylicacid tert-butyl ester

To a solution of(7R,9aS)-trans-7-(hydroxymethyl)-2-(tert-butoxycarbonyl)-2,3,4,6,7,8,9,9a-octahydro-1H-pyrido[1,2-a]pyrazine(European Patent Application EP 646,116, published Apr. 5, 1995; 8.5 g,31 mmol) in anhydrous tetrahydrofuran (120 ml), methyl 3-hydroxybenzoicacid (7.18 g, 47 mmol), triphenylphosphine (9.9 g, 38 mmol), anddiethylazodicarboxylate (5.94 ml, 38 mmol) were sequentially added. Thestirred reaction mixture was heated at 55° C. for 18 hours. The solventwas removed in vacuo, and the residue was extracted with a 10% diluteaqueous sodium bicarbonate/methylene chloride mixture (400 ml of each).The aqueous phase was extracted with three 100 ml portions of freshmethylene chloride. The combined organic extracts were in turn,extracted with 200 ml of 1N aqueous sodium hydroxide and 200 ml of 10%aqueous sodium bicarbonate, and then dried with anhydrous sodiumsulfate. Solvent removal in vacuo afforded an oil (30 g). The crudeproduct was purified by flash chromatography (silica gel, 47-61 micromesh; elution with ethyl acetate/hexane=6:4 in volume) which affordedthe title compound (9.36 g, 75% yield) as an amorphous solid.

¹³C NMR (75 MHz, CDCl₃) δ 166.9, 158.9, 154.6, 131.4, 129.4, 122.0,119.9, 114.6, 79.7, 71.1, 62.2, 60.8, 58.7, 54.8, 52.1, 36.3, 28.7,28.4, 26.9, 14.4 ppm; MS m/z 405 (M+1).

Step 2

(7R,9aS)-trans-7-(3-hydroxymethylphenoxymethyl)-octahydro-pyrido-[1,2-a]pyrazine-2-carboxylicacid tert-butyl ester

To an ice bath-chilled solution of the Step 1 title compound (9.36 g, 23mmol) in anhydrous ether (75 ml), a 1.0M solution of lithium aluminumhydride in diethyl ether (27.6 ml, 27.6 mmol) was added dropwise. Thereaction was then stirred for 40 minutes at ambient temperature prior toquenching by cautious dropwise addition of a total of 3 ml of 2N aqueoussodium hydroxide. Tetrahydrofuran (100 ml) was added, and the reactionwas stirred for 20 minutes prior to drying by addition of anhydroussodium sulfate. Filtration through a celite pad and solvent removal invacuo afforded the title compound as a colorless oil (quantitativeyield).

¹³C NMR (100 MHz; CDCl₃) δ 159.1, 142.9, 129.5, 119.1, 113.5, 112.9,79.7, 70.8, 67.9, 64.9, 62.1, 60.8, 58.6, 54.7, 36.2, 28.6, 28.4, 26.9,25.6, 14.4 ppm; MS m/z 377 (M+1).

Step 3

(7R,9aS)-trans-7-(3-pyrrolidin-1-ylmethyl-phenoxymethyl)-octahydro-pyrido[1,2-a]pyrazine-2-carboxylicacid tert-butyl ester

To an ice bath chilled solution of the title compound from the previousstep (5.6 g, 14.9 mmol) and triethylamine (2.60 ml, 18.6 mmol) inanhydrous methylene chloride (95 ml), methanesulfonyl chloride (1.27 ml,16.3 mmol) was added as a single portion. After 20 minutes of stirringat ca. 5° C., thin layer chromatography inspection (silica gel plates;methanol/methylene chloride=6:94 in volume; aqueous potassiumpermanganate spray with heat) revealed complete conversion of startingmaterial to the corresponding mesylate[(7R,9aS)-trans-7-(3-methanesulfonyloxymethyl-phenoxymethyl)-octahydro-pyrido[1,2-a]pyrazine-2-carboxylicacid tert-butyl ester]. 10% Aqueous sodium bicarbonate and methylenechloride (100 ml of each) were added, and the mixture was vigorouslystirred prior to phase separation. The aqueous phase was then extractedwith three 50 ml portion of fresh methylene chloride. The combinedorganic extracts were dried (anhydrous sodium sulfate), and the solventwas removed in vacuo to isolate the mesylate an oil. The entire samplewas dissolved in acetonitrile (95 ml). Pyrrolidine (3.88 ml, 44.7 mmol)was added, and the reaction mixture was then heated at 50° C. for 18hours. The solvent was removed in vacuo, and the resulting residue wasextracted into a 10% aqueous sodium bicarbonate/methylene chloride (200ml of each) mixture. The aqueous phase was re-extracted with three 50 mlportions of fresh methylene chloride. The combined organic extracts weredried (anhydrous sodium sulfate) and concentrated in vacuo to yield anamber oil (6.75 g). Flash chromatography of the entire sample (silicagel, 47-61 micron mesh; elution initially with methanol/methylenechloride=8:92 in volume, increasing methanol content to a final 2:8volume ratio) afforded the title compound (3.60 g, 56% yield) as acolorless oil.

¹³C NMR (75 MHz, CDCl₃) δ 159.1, 154.6, 129.2, 121.4, 115.0, 113.4,79.7, 70.9, 60.8, 60.5, 58.8, 54.8, 54.1, 50.7, 36.4, 28.8, 28.4, 26.9,23.4 ppm.

Step 4

(7R,9aS)-trans-3-(3-pyrrolidin-1-ylmethyl-phenoxymethyl)-octahydro-quinazolizinedihydrochloride

The Step 3 title compound (3.60 g) was dissolved in chloroform (50 ml).Diethyl ether (60 ml) saturated with anhydrous hydrogen chloride gas wasadded. The reaction mixture was then stirred at 18 hours at ambienttemperature. Evaporation of solvent and excess hydrogen chlorideafforded the title compound as a dihydrochloride salt (quantitativeyield).

Step 5

(7R,9aS)-trans-2-(5-fluoro-benzo[d]isoxazol-3-yl)-7-(3-pyrrolidin-1-ylmethyl-phenoxymethyl)-octahydro-pyrido[1,2-a]pyrazine

The Step 4 title compound (dihydrochloride salt; 125 mg, 0.31 mmol),1,8-diazabicyclo[5.4.0]-undec-7-ene (153 μl, 1.0 mmol), and3-chloro-5-fluoro-benzo[d]isoxazole (66 mg, 0.39 mmol) were dissolved inpyridine (150 μl). The reaction was heated at 90° C. for 18 hours. 10%aqueous sodium bicarbonate and methylene chloride (15 ml of each) wereadded to the well-stirred mixture. The aqueous phase was thenre-extracted with three 15 ml portions of fresh methylene chloride. Thecombined organic extracts were dried (anhydrous sodium sulfate) and thesolvent was removed in vacuo. Purification of the oily semi-solidresidue (150 mg) by flash chromatography (silica gel, 47-61 micron mesh;elution with methanol/methylene chloride=7.5:92.5 in volume) affordedthe title compound (free base) as a colorless amorphous solid (57 mg,36% yield). Dissolution of the entire sample in ethyl acetate/methylenechloride (1.0 ml of each), addition of a saturated diethyl ethersolution of anhydrous hydrogen chloride (3 ml); and finally, solventremoval in vacuo afforded the title compound dihydrochloride as anamorphous solid.

Free base data: ¹³C NMR (75 MHz, CDCl₃) δ 161.62, 160.91, 159.45,158.45, 141.54, 129.55, 121.70, 118.44, 116.88, 115.28, 113.35, 111.73,107.76, 71.26, 61.21, 60.55, 59.20, 54.68, 54.60, 54.12, 48.71, 36.88,29.43, 27.37, 23.90 ppm; MS m/z 465 (M+1).

EXAMPLE 6(7R,9aS)-TRANS-1-{3-[2-(5-FLUORO-BENZO[d]ISOXAZOL-3-YL)-OCTAHYDROPYRIDO[1,2-a]PYRAZIN-7-YLMETHOXY]-BENZYL}-AZETIDIN-3-OL(MIXTURE OF DIASTEREOMERS)

Step 1

(7R,9aS)-trans-7-[3-(3-hydroxy-azetidin-1-ylmethyl)-phenoxymethyl-octahydropyrido[1,2-a]pyrazine-2-carboxylicacid tert-butyl ester)

Utilizing the general procedure of Example 5, Step 3, and starting with2.25 g (6 mmol) of the aforedescribed Example 5/Step 2 title compoundand substituting as a reactant (R,S)-3-hydroxyazetidine for pyrrolidine,the title compound was isolated (free base) as a colorless oil (1.48 g,57% yield; flash chromatography purification: silica gel, 47-61 micronmesh; elution initially with methanol/methylene chloride=8:92 in volume,increasing methanol content to a final 2:8 volume ratio).

¹³C NMR (75 MHz, CDCl₃) δ 159.0, 154.6, 138.7, 129.4, 120.9, 114.5,113.5, 88.5, 79.7, 70.9, 64.1, 63.4, 62.5, 60.8, 58.8, 54.8, 36.3, 28.8,28.4, 26.9 ppm.

Step 2

(7R,9aS)-trans-1-[3-(octahydro-pyrido[1,2-a]pyrazin-7-ylmethoxy)-benzyl]-azetidin-3-oldihydrochloride

To a chloroform (20 ml) solution of the entire 1.48 g sample of thetitle compound of the previous step, diethyl ether saturated withanhydrous hydrogen chloride (25 ml) was added. The reaction was stirredat ambient temperature for 18 hours. Solvent removal in vacuo affordedthe title compound (qualitative yield) as an amorphous solid.

MS m/z 332 (M+1).

Step 3

(7R,9aS)-trans-1-{3-[2-(5-fluoro-benzo[d]isoxazol-3-yl)-octahydro-pyrido[1.2-a]pyrazin-7-ylmethoxy]-benzyl}-azetidin-3-ol(mixture of diastereomers)

The title compound (dihydrochloride salt) prepared in the previous step(205 mg, 0.51 mmol), 1,8-diazabicyclo[5.4.0]undec-7-ene (251 μl, 1.66mmol), and 3-chloro-5-fluoro-benzo[d]isoxazole (110 mg, 0.64 mmol) werecombined in anhydrous pyridine (250 μl). The resulting solution washeated at 90° C. for 18 hours. 10% aqueous sodium bicarbonate andmethylene chloride (20 ml) of each were added, and the mixture wasvigorously stirred. The aqueous phase was then extracted with three 20ml portions of fresh methylene chloride. The combined organic extractswere dried (anhydrous sodium sulfate) and concentrated in vacuo to yieldan amber oil (240 mg). Flash chromatography using the entire sample(silica gel, 47-61 micron mesh; elution with methanol/methylenechloride=1:9 in volume) afforded the (free base) title compound (40 mg,17% yield) as a colorless amorphous solid.

MS m/z 467 (M+1).

EXAMPLE 7(7R,9aS)-TRANS-2-(5-FLUORO-BENZO[d]ISOXAZOL-3-YL)-7-(3-MORPHOLIN-4-YLMETHYLPHENOXYMETHYL)-OCTAHYDRO-PYRIDO[1,2-a]PYRAZINE

Step 1

(7R,9aS)-trans-7-(3-morpholin-4-ylmethylphenoxymethyl)-octahydro-pyrido[1,2-a]pyrazine-2-carboxylicacid tert-butyl ester

Utilizing the general procedure of Example 5, Step 3, and the product ofExample 1, Step 2 (600 mg, 1.59 mmol) and substituting morpholine (419μl, 4.77 mmol) for pyrrolidine as a reactant, the title compound wasprepared as a colorless oil (354 mg, 50% yield; flash chromatography:silica gel, 47-61 micron mesh; elution with methanol/methylene chloride4:96 in volume).

¹³C NMR (100 MHz, CDCl₃) δ 158.9, 154.5, 139.4, 129.1, 121.4, 115.1,113.0, 79.6, 70.7, 66.9, 63.3, 60.7, 58.7, 54.7, 53.6, 36.3, 28.7, 28.4,26.9 ppm. MS m/z 446 (M+1).

Step 2

(7R,9aS)-trans-7-(3-morpholin-4-ylmethyl-phenoxymethyl)-octahydro-pyrido[1,2-a]pyrazinedihydrochloride

Utilizing the general procedure of Example 5, Step 4, and substitutingas a reactant the product of the previous step (350 mg), the titlecompound was prepared (dihydrochloride salt) as an amorphrous foam(quantitative yield).

Step 3

(7R,9aS)-trans-2-(5-fluoro-benzo[d]isoxazol-3-yl)-7-(3-morpholin-4-ylmethyl-phenoxymethyl)-octahydro-pyrido[1,2-a]pyrazine

Utilizing the general procedure of Example 5, step 5, and substitutingthe product of the previous step (dihydrochloride) as a reactant (250mg, 0.60 mmol), with appropriate scaling of other reactants/solvents,the title compound was prepared (107 mg, 37% yield) as a colorless,amorphous solid. (Flash chromatography: silica gel, 47-61 micron mesh;elution with methanol/methylene chloride=4:96 in volume).

¹³C NMR (100 MHz, CDCl₃) δ 161.5, 160.3, 160.0, 140.3, 130.0, 122.3,118.9, 118.6, 115.9, 113.8, 112.0, 111.9, 108.1, 107.8, 71.2, 68.7,67.4, 63.8, 60.4, 59.0, 54.4, 53.9, 48.5, 36.6, 29.1, 27.0 ppm; MS m/z481 (M+1).

EXAMPLE 8(7R,9aS)-TRANS-2-(5-FLUORO-BENZO[d]ISOXAZOL-3-YL-7-(3-PYRROLIDIN-1-YLMETHYL-PHENOXYMETHYL)-OCTAHYDRO-PYRIDO[1,2-a]PYRAZINE

Step 1

(7R,9aS)-trans-[2-(5-fluoro-benzo[d]isoxazol-3-yl)-octahydro-pyrido-1,2-a]pyrazin-7-yl]-methanol

(Octahydro-quinazolin-3-yl)-methanol (5.42 g, 26.2 mmol),1,8-diazobicyclo[5.4.0]-undec-7-ene (12.9 ml, 85 mmol), and3-chloro-5-fluoro-benzo[d]isoxazole (5.54 g, 32.3 mmol) were dissolvedin pyridine (16 ml), and then heated (110° C.) with stirring for 18hours. 10% aqueous sodium bicarbonate and methylene chloride (250 ml ofeach) were added, and the mixture was vigorously stirred. The aqueousphase was then re-extracted with three 100 ml portions of freshmethylene chloride. The combined organic extracts were dried (anhydroussodium sulfate) and concentrated in vacuo to an amorphous solid (4.88g). Flash chromatography of the entire sample (silica gel, 47-61 micronmesh; elution with methanol/methylene chloride=6.94 in volume) affordedthe title compound (3.46 g, 43% yield) as an amorphous solid.

MS m/z 306 (M+1).

Step 2

(7S,9aS)-trans-3-[2-(5-fluoro-benzo[d]isoxazol-3-yl)-octahydro-pyrido[1,2-a]pyrazin-7-ylmethoxy]-benzoicacid methyl ester

To a solution of the title compound of the previous step (3.46 g, 11mmol), methyl-3-hydroxybenzoate (2.58 g, 17 mmol),diethylazodicarboxylate (2.08 ml, 13.2 mmol), and triphenylphosphine(3.46 g, 13.2 mmol) were combined in tetrahydrofuran (50 ml). Thesolution was heated (50° C.) and stirred for 18 hours. 10% aqueoussodium bicarbonate and methylene chloride (100 ml of each) were added,and the mixture was vigorously stirred. The aqueous phase was thenre-extracted with three 50 ml portions of fresh methylene chloride. Thecombined organic extracts were, in turn, sequentially extracted with 1 Naqueous sodium hydroxide and 10% aqueous sodium bicarbonate. Theseparated organic phase was dried (anhydrous sodium sulfate) and thesolvent was removed in vacuo, yielding a tacky solid (12.75 g). Flashchromatography of the entire sample (silica gel, 47-61 micro mesh;elution with methanol/methylene chloride=4:96 in volume) afforded thetitle compound (2.90 g, 60% yield) as colorless amorphous solid.

MS m/z 440 (M+1).

Step 3

(7R,9aS)-trans-{3-[2-(5-fluoro-benzo[d]isoxazol-3-yl)-octahydro-pyrido[1,2-a]pyrazin-7-ylmethoxy]-phenyl}-methanol

To a well stirred, ice bath-chilled partial solution of the titlecompound of the previous step (2.90 g, 6.6 mmol) in diethylether (25ml)/tetrahydrofuran (30 ml), a 1.0M diethyl ether solution of lithiumaluminum hydride (8.25 ml, 8.25 mmol) was added dropwise. The reactionmixture was then vigorously stirred at ambient for 1 hour beforequenching by cautious dropwise addition (at 5-10° C.) of a total of 1 ml1 N aqueous sodium hydroxide. After stirring at ambient temperature for30 minutes, the mixture was dried with anhydrous sodium sulfate and thenfiltered through celite. Solvent removal in vacuo afforded an oil (3.6g). Flash chromatography of the entire sample (silica gel, 47-61 micronmesh; elution with methanol/methylene chloride=6:94 in volume) affordedthe title compound (in free base form) as a colorless amorphous solid(1.83 g; 67% yield).

¹³C NMR (75 MHz, CDCl₃) δ 160.5, 159.2, 142.6, 129.6, 119.2, 118.2,117.9, 113.7, 112.9, 111.4, 111.3, 107.4, 107.1, 70.9, 65.2, 60.1, 58.6,54.1, 53.6, 48.2, 36.3, 28.9, 26.9 ppm. MS m/z 412 (M+1).

Step 4

(7R,9aS)-trans-{3-[2-(5-fluoro-benzo[d]isoxazol-3-yl)-octahydro-pyrido[1,2-a]pyrazin-7-ylmethoxy]-phenyl}-methanolmethane sulfonate

To a well-stirred mixture of the title compound (440 mg, 1.07 mmol) ofthe previous step (partially dissolved) and triethylamine (186 μl, 1.34mmol) in methylene chloride (10 ml), at ambient temperature,methanesulfonyl chloride (91 μl, 1.18 mmol) was added. After stirringfor 20 minutes, additional portions of triethylamine (18.6 μl, 0.13mmol) and methanesulfonyl chloride (9.1 μl, 0.12 mmol) were added. Thereaction was then stirred for an additional 20 minutes before quenchingwith 10% aqueous sodium bicarbonate (with 20 ml of methylene chlorideadded). The reaction mixture was extracted with three 10 ml freshportions of methylene chloride. The combined organic extracts were dried(anhydrous sodium sulfate) and concentrated in vacuo to afford the titlecompound as a viscous oil (528 mg, quantitative yield). The product wasused in the next step without further purification.

MS m/z 490 (M+1).

Step 5

(7R,9aS)-trans-2-(5-fluoro-benzo[d]isoxazol-3-yl-7-(3-pyrrolidin-1-ylmethyl-phenoxymethyl)-octahydro-pyrido[1.2-a]pyrazine(free base)

A reaction mixture consisting of the mesylate title compound from theprevious step (79 mg, 0.16 mmol) and pyrrolidine (42 μl, 0.48 mmol) inacetonitrile (2 ml) was stirred at 55° C. for 18 hours. The solvent wasremoved in vacuo, and the residue was extracted into a 10% aqueoussodium bicarbonate/methylene chloride biphasic mixture (20 ml of each).The organic phase was then extracted with three 10 ml portions of freshmethylene chloride. The combined organic extracts were dried (anhydroussodium sulfate), and then concentrated in vacuo to afford a colorlessamorphous solid (100 mg). Successive pulping of the pulverized solidwith two 15 ml portions of hexanes (with careful pipette siphoning offof each hexane extract after pulping) afforded the title compound as acolorless amorphous solid (60 mg, 81% yield). This product was identicalin all respects to the amorphous free base title compound product ofExample 5/Step 5.

EXAMPLE 9(7R,9aS)-TRANS-2-(4-FLUORO-BENZO[d]ISOXAZOL-3-YL)-7-(3-PYRROLIDIN-1-YLMETHYL-PHENOXYMETHYL)-OCTAHYDRO-PYRIDO[1,2-a]PYRAZINE

Utilizing the general procedure of Example 5, Step 5 and the product ofExample 5, Step 4(337 mg, 0.84 mmol) and3-chloro-4-fluoro-benzo[d]isoxazole (180 mg, 1.05 mmol) as reactants,and with appropriate scaling of other reagents/solvents, the titlecompound (90 mg, 23% yield) was obtained as a viscous oil. Flashchromatography: silica gel, 47-61 micron mesh; elution initially withmethanol/methylene chloride—6:94 in volume, increasing methanol contentto a final 1:9 volume ratio (90 mg, 23% yield).

MS m/z 465 (M+1).

EXAMPLE 10(7S,9aS)-CIS-2-BENZO[d]ISOXAZOL-3-YL-7-(3-PYRROLIDIN-1-YLMETHYL-PHENOXYMETHYL)-OCTAHYDRO-PYRIDO-[1,2-a]PYRAZINE

Step 1

(7S,9aS)-cis-3-(2-Benzo[d]isoxazol-3-yl-octahydro-pyrido[1,2-a]pyrazin-7-ylmethoxy)-benzoicacid methyl ester

To a well-stirred solution consisting of(7S,9aS)-cis-(2-Benzo[d]isoxazol-3-yl-octahydro-pyrido[1,2-a]pyrazin-7-yl)-methanol(3.40 g, 11.83 mmol), methyl-3-hydroxybenzoate (2.70 g, 17.75 mmol), andtriphenylphosphine (3.70 g, 14.20 mmol), in anhydrous tetrahydrofuran(68 ml), diethylazodicarboxylate (2.24 ml, 14.20 mmol) was added. Theresulting solution was heated at 50° C. for 2 hours. The solvent wasremoved in vacuo, and the resulting residue was extracted into abiphasic 1N aqueous sodium hydroxide (40 ml)/methylene chloride (50 ml)mixture. The aqueous phase was twice extracted with equal volumeportions of fresh methylene chloride. The combined organic extracts weredried (anhydrous magnesium sulfate), and concentrated to an amber oil.An initial flash chromatography (silica gel, 70-230 micron mesh; elutionwith methanol/methylene chloride=1:99 in volume) afforded partiallypurified product (3.3 g, contaminants: hydrazine diethylcarboxylate andtriphenylphosphine oxide). A second flash chromatography of the entiresample (silica gel, 230-400 micron mesh, elution with methanol/methylenechloride=1:99) afforded the purified title compound (1.37 g, 27% yield)as a colorless amorphous solid.

MS m/z 422 (M+1). ¹³C NMR (75 MHz, CDCl₃) δ 167.1, 164.0, 161.1, 159.3,131.4, 129.5, 129.3, 122.2 (2), 121.8, 120.1, 116.2, 114.8, 110.5, 69.0,60.4, 56.4, 54.2, 53.7, 52.2, 48.3, 33.7, 25.1, 24.7 ppm.

Step 2

(7S,9aS)-cis-[3-(2-Benzo[d]isoxazol-3-yl-octahydro-pyrido[1,2-a]pyrazin-7-ylmethoxy)-phenyl]-methanol

To a well-stirred, ice bath-chilled solution of the title compound ofStep 1 (1.33 g, 3.16 mmol) in anhydrous tetrahydrofuran (nitrogenatmosphere), a 1.0M solution of lithium aluminum hydride (3.80 ml, 3.80mmol) was added dropwise over 10 minutes. The reaction was stirred at 5°C. for 30 minutes, and then at ambient temperature for 1 hour.Subsequently, with ice bath chilling, the reaction was quenched by slow,dropwise addition of aqueous 1N sodium hydroxide (exotherm). After 15minutes of stirring at ambient temperature, solid anhydrous sodiumsulfate was added. The mixture was filtered through celite, and thefiltrate was concentrated in vacuo to yield a colorless oil. Flashchromatography of the entire sample (silica gel, 230-400 micron mesh;elution with methanol/methylene chloride=2:98 in volume) afforded thetitle compound (891 mg, 72% yield) as a colorless amorphous solid.

MS m/z 394 (M+1); ¹³C NMR (75 MHz CDCl₃) δ 164.0, 161.1, 159.6, 142.5,129.6, 129.5, 122.2 (2), 118.9, 116.2, 114.0, 112.9, 110.5, 68.8, 65.3,60.4, 56.5, 54.2, 53.7, 48.3, 33.7, 25.1, 24.8 ppm.

Step 3

(7S,9aS)-cis-2-Benzo[d]isoxazol-3-yl-7-(3-pyrrolidin-1-ylmethyl-phenoxymethyl)-octahydro-pyrido[1,2-a]pyrazine.

Utilizing the title compound of Step 2 (300 mg, 0.76 mmol),triethylamine (0.118 ml, 0.91 mmol) methanesulfonyl chloride (0.063 ml,0.81 mmol) as reactants and methylene chloride (6.0 ml) as solvent, thecorresponding mesylate of the Step 2 product was prepared in situ usingthe method of Example 8, Step 4.

A one-third (by volume) portion of the in situ generated mesylatesolution (approximately 0.25 mmol of mesylate) and pyrrolidine (0.064ml, 0.76 mmol) were combined in acetonitrile (2 ml). The reaction wasrefluxed for 3 hours; then stirred at ambient temperature for 18 hours.The solvent was removed in vacuo, and the residue was extracted into abiphasic methylene chloride/saturated aqueous sodium bicarbonate mixture(60 ml of each). The aqueous phase was extracted with two equal volumeportions of fresh methylene chloride. The combined organic extracts weredried (anhydrous sodium sulfate) and concentrated in vacuo, yielding asolid residue. Flash chromatography of the entire sample (silica gel,47-61 micron mesh; elution with methylene chloride/methanol/concentratedaqueous ammonium hydroxide—18:1:0.04 in volume) afforded the titlecompound (60 mg, 54% yield) as a colorless amorphous solid.

¹³C NMR (CDCl₃) δ 164.0, 161.1, 159.3, 141.0, 129.5, 129.1, 122.2,121.1, 116.2, 115.0, 113.2, 110.5, 68.7, 65.8, 60.8, 60.4, 56.5, 54.2,53.7, 48.3, 33.8, 25.2, 24.8, 23.5 ppm.

EXAMPLE 11(7S,9aS)-CIS-1-[3-(2-BENZO[d]ISOXAZOL-3-YL-OCTAHYDRO-PYRIDO[1,2-a]PYRAZIN-7-YLMETHOXY)-BENZYL]PYRROLIDINE-3,4-DIOL

To a well-stirred, ice bath chilled solution of the title compound ofExample 10, Step 2, 254 mg (0.65 mmol) in dichloromethane (5 ml),triethylamine (112 μl, 0.81 mmol) and methanesulfonyl chloride (55 μl,0.71 mmol) were added; and the resulting mixture was stirred for 20minutes at ambient temperature. Thin layer chromatography inspectionindicated complete reaction (mesylate formation). Methylene chloride (25ml) was added, and the mixture was then extracted with 25 ml of dilute(ca. 10%) aqueous sodium bicarbonate. The aqueous phase was thenextracted with several equal volume fresh portions of methylenechloride. The combined organic extracts were concentrated in vacuo toafford the mesylate of the Example 10, step 2 product as an amorphousfoam. The entire mesylate sample and trans-3,4-dihydroxy pyrrolidine(derived from D-tartaric acid 200 mg, 1.93 mmol) was dissolved inacetonitrile/N,N-dimethylformamide (5 ml and 1.5 ml, respectively). Thesolution was then stirred at 50° C. for 18 hours. The solvent wasremoved in vacuo, and the residue was extracted with 10% aqueous sodiumbicarbonate/methylene chloride (20 ml of each). The separated aqueousphase was extracted with three fresh equal volume portions of methylenechloride. The combined organic extracts were dried (anhydrous sodiumsulfate) and concentrated in vacuo to afford an oil (420 mg). Flashchromatography (silica gel; 47-61 micron mesh; elution withmethanol/methylene chloride=9:91 in volume) afforded the free base formof the title compound as a colorless amorphous foam (110 mg; 35% yield).

EXAMPLE 12(7S,9aS)-CIS-2-BENZO[d]ISOXAZOL-3-YL-7-(2-METHYL-5-PYRROLIDIN-1-YLMETHYL-PHENOXYMETHYL)-OCTAHYDRO-PYRIDO[1,2-a]PYRAZINE

Step 1

(7S,9aS)-cis-3-(2-Benzo[d]isoxazol-3-yl-octahydro-pyrido[1,2-a]pyrazin-7-ylmethoxy)-4-methyl-benzoicacid methyl ester

To a solution of(7S,9aS)-cis-(2-Benzo[d]isoxazol-3-yl-octahydro-pyrido[1,2-a]pyrazin-7-yl)-methanol(500 mg, 1.7 mmol), 3-hydroxy-4-methyl-benzoic acid methyl ester (432mg, 2.6 mmol) and triphenylphosphine (525 mg, 2.0 mmol) intetrahydrofuran (10 ml), diethylazodicarboxylate (315 μl, 2.0 mmol) wasadded. The reaction mixture was then stirred at 50° C. for 2 hours. Thesolvent was removed and the residue was extracted with a 10% sodiumbicarbonate/methylene chloride (20 ml of each) biphasic mixture. Theaqueous phase was then extracted with three 10 ml portions of freshmethylene chloride. The combined organic extracts were dried (anhydroussodium sulfate), and concentrated in vacuo to an orange oil (2.01 g).Flash chromatography of the entire sample (silica gel, 47-61 micronmesh; elution with ethyl acetate/hexanes=2:8 in volume) afforded thetitle compound (267 mg, 36% yield) as an amorphous solid.

¹³C NMR (75 MHz CDCl₃) δ 167.5, 164.0, 161.2, 157.2, 132.6, 130.3,129.4, 128.9, 122.2, 121.7, 116.2, 111.6, 110.5, 68.9, 60.5, 56.6, 54.2,53.7, 52.0, 48.3, 33.8, 25.1, 24.8, 16.6 ppm. MS m/z 436 (M+1).

Step 2

(7S,9aS)-cis-[3-(2-Benzo[d]isoxazol-3-yl-octahydro-pyrido[1,2-a]pyrazin-7-ylmethoxy)-4-methyl-phenyl]-methanol

Utilizing the general procedure of Example 10, Step 2, theabove-described Step 1 product (267 mg, 0.61 mmol) was converted to thetitle compound, isolated as a colorless oil (239 mg, 58% yield).

MS m/z 408 (M+1).

Step 3

(7S,9aS)-cis-2-Benzo[d]isoxazol-3-yl-7-(2-methyl-5-pyrrolidin-1-ylmethyl-phenoxymethyl)-octahydro-pyrido[1,2-a]pyrazine

By the general procedure of Example 10, Step 3, the above-described Step2 product (140 mg, 0.34 mmol) was converted into the title compound (22mg, 14% yield), isolated as a colorless amorphous solid.

¹³C NMR (75 MHz CDCl₃) δ 164.0, 162.0, 157.4, 130.2, 129.4, 125.5,122.2, 120.7, 116.3, 111.9, 110.5, 68.7, 60.7, 60.5, 56.6, 54.3, 54.1,53.7, 48.3, 33.9, 25.2, 24.8, 23.4, 16.1 ppm; MS m/z 461 (M+1).

EXAMPLE 13(7S,9aS)-CIS-2-BENZO[d]ISOXAZOL-3-YL-7-(3-METHOXY-5-PYRROLIDIN-1-YLMETHYL-PHENOXYMETHYL)-OCTAHYDRO-PYRIDO[1,2-a]PYRAZINE

Step 1

(7S,9aS)-cis-3-(2-Benzo[d]isoxazol-3-yl-octahydro-pyrido[1,2-a]pyrazin-7-ylmethoxy)-5-methoxy-benzoicacid methyl ester

Utilizing the general procedure of Example 11, above and(7S,9aS)-cis-(2-Benzo[d]isoxazol-3-yl-octahydro-pyrido[1,2-a]pyrazin-7-yl)-methanol(500 mg, 1.7 mmol), and 3-methoxy-5-hydroxy benzoic acid methyl ester(475 mg, 2.6 mmol) as reactants, the title compound was prepared andisolated as a colorless oil (363 mg, 47% yield).

MS m/z=452 (M+1).

Step 2

(7S,9aS)-cis-[3-(2-Benzo[d]isoxazol-3-yl-octahydro-pyrido[1,2-a]pyrazin-7-ylmethoxy)-5-methoxy-phenyl]-methanol

Utilizing the general procedure of Example 10, Step 2, theabove-described Step 1 product (363 mg, 0.8 mmol) was converted to thetitle compound, isolated as a colorless oil (247 mg, 73% yield).

¹³C NMR (75 MHz, CDCl₃) δ 164.0, 161.1, 161.0, 160.6, 143.5, 129.5,122.3, 122.2, 116.2, 110.5, 105.2, 104.5, 100.2, 68.9, 65.2, 60.4, 56.4,55.4, 54.2, 53.6, 48.2, 33.7, 30.3, 29.9, 25.1, 24.7 ppm. MS m/z 424(M+1).

Step 3

(7S,9aS)-cis-2-Benzo[d]isoxazol-3-yl-7-(3-methoxy-5-pyrrolidin-1-ylmethyl-phenoxymethyl)-octahydro-pyrido[1,2-a]pyrazine

By the general procedure of Example 10, Step 3, the above-described Step2 product (240 mg, 0.57 mmol) as converted into the title compound (209mg, 70% yield), isolated as a colorless oil.

¹³C NMR (75 MHz, CDCl₃) δ 164.0, 161.1, 160.7, 106.4, 141.7, 129.5,122.2, 116.2, 110.4, 107.3, 106.7, 99.7, 68.8, 61.0, 60.4, 56.5, 55.3,54.2, 53.7, 48.3, 33.8, 25.2, 24.8, 23.5 ppm; MS m/z 477 (M+1).

EXAMPLE 14(7S,9aS)-CIS-2-BENZO[d]ISOXAZOL-3-YL-7-(4-CHLORO-3-PYRROLIDIN-1-YLMETHYL-PHENOXYMETHYL)-OCTAHYDRO-PYRIDO[1,2-a]PYRAZINE

Step 1

(7S,9aS)-cis-5-(2-Benzo[d]isoxazol-3-yl-octahydro-pyrido[1,2-a]pyrazin-7-ylmethoxy)-2-chlorobenzoicacid methyl ester

Utilizing the general procedure of Example 10, Step 1 above, and(7S,9aS)-cis-(2-Benzo[d]isoxazol-3-yl-octahydro-pyrido[1,2-a]pyrazin-7-yl)-methanol(126 mg, 0.44 mmol) and 2-chloro-5-hydroxy-benzoic acid methyl ester(115 mg, 0.62 mmol) as reactants, the title compound was prepared andisolated as a colorless oil (690 mg; 20% yield).

MS m/z 456 (M).

Step 2

(7S,9aS)-cis-[5-(2-Benzo[d]isoxazol-3-yl-octahydro-pyrido[1,2-a]pyrazin-7-ylmethoxy)-2-chloro-phenyl]-methanol

Utilizing the general procedure of Example 10, Step 2, theabove-described Step 1 product (40 mg, 0.09 mmol) was converted to thetitle compound in quantitative yield, isolated as a colorless oil.

Step 3

(7S,9aS)-cis-2-Benzo[d]isoxazol-3-yl-7-(4-chloro-3-pyrrolidin-1-ylmethyl-phenoxymethyl)octahydro-pyrido[1.2-a]pyrazine

By the general procedure of Example 10, Step 3, the above-described Step2 product (54 mg, 0.13 mmol) was converted into the title compound (6mg, 10% yield), isolated as a colorless oil.

EXAMPLE 15(7S,9aS)-CIS-2-BENZO[d]ISOXAZOL-3-YL-7-(4-PYRROLIDIN-1-YLMETHYL-PHENOXYMETHYL)-OCTAHYDRO-PYRIDO[1,2-a]PYRAZINE

Step 1

(7S,9aS)-cis-4-(2-Benzo[d]isoxazol-3-yl-octahydro-pyrido[1,2-a]-pyrazin-7-ylmethoxy)-benzoicacid methyl ester

To a well-stirred solution consisting of(7S,9aS)-cis-(2-Benzo[d]isoxazol-3-yl-octahydro-pyrido[1,2-a]pyrazin-7-yl)-methanol(3.49 g, 12.1 mmol), methyl-4-hydroxybenzoate (Aldrich Chemical Co.,2.80 g, 18.2 mmol), and triphenylphosphine (3.80 g, 14.6 mmol) inanhydrous tetrahydrofuran (70 ml), diethylazodicarboxylate (2.29 ml,14.6 mmol) was added. After heating the solution for two hours at 50°C., the solvent was removed in vacuo. The residue was extracted into abiphasic 1 N aqueous sodium hydroxide (40 ml)/methylene chloride (50 ml)mixture. The aqueous phase was twice extracted with equal volumeportions of methylene chloride. The combined organic extracts were dried(anhydrous magnesium sulfate), and concentrated in vacuo, yielding anamber oil. Flash chromatography of the entire sample (silica gel, 70-230micron mesh; elution with methanol/methylene chloride=0.5:95.5 involume) afforded the title compound (3.20 g, 63% yield) as a colorlessamorphous solid.

MS m/z 422 (M+1); ¹³C NMR (75 MHz, CDCl₃) δ 166.9, 164.0, 163.1, 131.6,129.5, 122.4, 122.2 (2), 116.2, 114.2, 110.5, 62.2, 60.4, 56.4, 54.2,53.7, 51.8, 48.3, 33.7, 25.1, 24.7 ppm.

Step 2

(7S,9aS)-cis-[4-(2-Benzo[d]isoxazol-3-yl-octahydro-pyrido[1,2-a]pyrazin-7-ylmethoxy)-phenyl]-methanol

To an ice bath chilled solution of the title compound from Step 1 (1.50mg, 3.56 mmol) in anhydrous tetrahydrofuran (nitrogen atmosphere), atotal of 4.30 ml (4.27 mmol) of a 1.0M solution of lithium aluminumhydride was added dropwise over 10 minutes. The reaction was stirred at5° C. for 30 minutes, and then at ambient temperature for 1 hour.Finally, the reaction was quenched (5° C.) by cautious addition of 500μl of 1N aqueous sodium hydroxide. Solid anhydrous sodium sulfate wasadded, and the mixture was filtered through celite. The filtrate wasconcentrated in vacuo, yielding an amorphous solid (1.36 g). Flashchromatography of the entire sample (silica gel, 230-400 micron mesh;elution with methanol/methylene chloride=2:98 in volume) afforded thetitle compound as a colorless amorphous solid (0.96 g, 68.6% yield).

MS m/z 394 (M+1); ¹³C NMR (75 MHz, CDCl₃) δ 164.0, 161.1, 158.9, 133.0,129.5, 128.6, 122.2 (2), 110.5, 114.7, 116.2, 68.9, 65.1, 60.4, 56.5,54.2, 53.7, 48.3, 33.7, 25.1, 24.7 ppm.

Step 3

(7S,9aS)-cis-2-Benzo[d]isoxazol-3-yl-7-(4-chloromethyl-phenoxymethyl)-octahydro-pyrido[1,2-a]pyrazine

To an ice bath-chilled solution of the title compound of the previousstep (1.00 g, 2.54 mmol) and triethylamine (442 μl, 3.17 mmol) inmethylene chloride (22 ml), methanesulfonyl chloride 216 μl (2.80 mmol)was added. After 1 hour of stirring at 5° C., additional portions oftriethylamine (442 μl) and methanesulfonyl chloride (216 μl) were added.TLC inspection of a reaction aliquot (silica gel plates; elution withmethanol/methylene chloride=1:9 in volume, UV detection) indicatedincomplete reaction. The reaction was then stirred at ambienttemperature, at which time, a third addition of triethylamine (442 μl)and methanesulfonyl chloride (216 μl) was made. After 1.5 hours ofstirring at ambient temperature, TLC inspection indicated completereaction. The reaction was then vigorously stirred after addition ofsaturated aqueous sodium bicarbonate and methylene chloride (20 ml ofeach). The aqueous phase was extracted with an equal volume of freshmethylene chloride. The combined organic extracts were dried (anhydrousmagnesium sulfate) and concentrated in vacuo to afford the titlecompound as an amorphous solid (1.85 g), used in the next step withoutfurther purification.

MS m/z 412 (M+1).

Step 4

(7S,9aS)-cis-2-Benzo[d]isoxazol-3-yl-7-(4-pyrrolidin-1-ylmethyl-phenoxymethyl)-octahydro-pyrido[1,2-a]pyrazine

A solution consisting of the title compound from the previous step (50mg, 0.12 mmol) and pyrrolidine (32.8 μl, 0.38 mmol) in acetonitrile(1.00 ml) was heated at 50° C. for 2.5 hours. The solvent was removed invacuo, and the residue was extracted into a saturated aqueous sodiumbicarbonate/methylene chloride biphasic mixture. The aqueous phase wasextracted twice with equal volume portions of fresh methylene chloride.The combined organic extracts were dried (anhydrous magnesium sulfate)and concentrated in vacuo to yield an amorphous solid. Flashchromatography of the entire sample (silica gel, 230-400 micron mesh;elution with methanol/methylene chloride=5:95 in volume) afforded thetitle compound (35 mg, 61.4% yield) as a colorless amorphous solid.

MS m/z 447 (M+1).

Utilizing the methods of Examples 10-15, and the title compound fromExample 10, Step 2 as the reactant, and utilizing the specified finalstep amine reactant, the title compounds of Examples 16-28 wereprepared.

EXAMPLE 16(7S,9aS)-CIS-7-(3-AZETIDIN-1-YLMETHYL-PHENOXYMETHYL)-2-BENZO[d]ISOXAZOL-3-YL-OCTAHYDRO-PYRIDO[1,2-a]PYRAZINE

Final step amine reactant: azetidine; final step yield: 35% (colorlessamorphous solid);

¹³C NMR (75 MHz, CDCl₃) δ 164.0, 161.1, 159.4, 139.9, 129.4, 129.2,122.2, 120.7, 116.2, 114.4, 113.4, 110.5, 68.7, 64.0, 60.4, 56.5, 55.2,54.2, 53.7, 48.3, 33.8, 25.2, 24.8, 17.7 ppm; MS m/z 433 (M+1).

EXAMPLE 17(7S,9aS)-CIS-[3-(2-BENZO[d]ISOXAZOL-3-YL-OCTAHYDRO-PYRIDO[1,2-a]PYRAZIN-7-YLMETHOXY)-BENZYL]-CYCLOPROPYLMETHYL-AMINE

Final step amine reactant: cyclopropylmethyl amine; final step yield:23% (colorless oil);

¹³C NMR (75 MHz, CDCl₃) δ 164.0, 161.1, 159.4, 142.0, 129.5, 129.3,122.2, 120.3, 116.2, 114.2, 113.2, 110.5, 68.7, 60.4, 56.5, 54.5, 54.2,53.8, 53.7, 48.3, 33.8, 25.2, 24.8, 11.2 ppm.

EXAMPLE 18(7S,9aS)-CIS-2-BENZO[d]ISOXAZOL-3-YL-7-[3-(2-METHOXYMETHYL-PYRROLIDINE-1-YLMETHYL)-PHENOXYMETHYL]-OCTAHYDRO-PYRIDO[1,2-a]PYRAZINE

Final step amine reactant: 2S-methoxymethyl-pyrrolidine; final stepyield: 20% (colorless oil);

¹³C NMR (CDCl₃) δ 164.0, 161.1, 159.2, 141.4, 129.5, 129.0, 122.2,121.2, 116.2, 115.3, 112.8, 110.5, 68.7, 63.1, 60.4, 59.7, 59.1, 56.5,54.7, 54.2, 53.7, 48.3, 33.8, 28.6, 25.2, 24.8, 22.8 ppm; MS m/z 490(M+1).

EXAMPLE 19(7S,9aS)-CIS-[3-(2-BENZO[d]ISOXAZOL-3-YL-OCTAHYDRO-PYRIDO[1,2-a]PYRAZIN-7-YLMETHOXY)-BENZYL]-CYCLOPROPYL-AMINE

Final step amine reactant: cyclopropylamine (Aldrich Chem. Co.); finalstep yield: 32% (colorless oil);

¹³C NMR (75 MHz, CDCl₃) δ 164.0, 161.4, 159.4, 142.2, 129.5, 129.3,122.2, 120.3, 116.3, 114.4, 113.0, 110.5, 68.7, 60.4, 56.5, 54.2, 53.7,48.3, 33.8, 30.1, 25.2, 24.8, 6.6, 6.4 ppm.

EXAMPLE 20(7S,9aS)-CIS-2-BENZO[d]ISOXAZOL-3-YL-7-(3-PYRROLIDIN-1-YLMETHYL-PHENOXYMETHYL)-OCTAHYDRO-PYRIDO[1,2-a]PYRAZINE

Final step amine reactant: pyrrolidine; final step yield: 18% (colorlessamorphous solid); ¹³C NMR (75 MHz, CDCl₃) δ 164.0, 161.1, 159.3, 141.0,129.5, 129.1, 122.2, 121.1, 116.2, 115.0, 113.2, 110.5, 68.7, 60.8,60.4, 56.5, 54.2, 53.7, 48.3, 33.8, 25.2, 24.8, 23.5 ppm.

EXAMPLE 21(7S,9aS)-CIS-2-BENZO[d]ISOXAZOL-3-YL-7-[3-(4-ETHYL-PIPERAZIN-1-YLMETHYL)-PHENOXYMETHYL]-OCTAHYDRO-PYRIDO[1,2-a]PYRAZINE

Final step amine reactant: 1-ethyl-piperazine; final step yield: 17%(colorless amorphous solid);

¹³C NMR (75 MHz, CDCl₃) δ 164.0, 161.1, 159.3, 139.8, 129.5, 129.1,122.2, 121.4, 116.2, 115.4, 113.1, 110.5, 68.7, 63.1, 60.4, 56.5, 54.2,53.7, 53.1, 52.8, 52.3, 48.3, 33.8, 25.2, 24.8, 12.0 ppm; MS m/z 490(M+1).

EXAMPLE 22(7S,9aS)-CIS-[3-(2-BENZO[d]ISOXAZOL-3-YL-OCTAHYDRO-PYRIDO[1,2-a]PYRAZIN-7-YLMETHOXY)-BENZYL]-CYCLOHEXYL-AMINE

Final step amine reactant: cyclohexylamine; final step yield: 19%(colorless amorphous solid);

¹³C NMR (75 MHz, CDCl₃) δ 164.0, 161.1, 159.4, 142.6, 129.4, 129.3,122.2, 120.3, 116.2, 114.3, 113.0, 110.5, 68.7, 60.4, 56.5, 56.2, 54.2,53.7, 51.1, 48.3, 33.8, 33.6, 26.2, 25.2, 25.0, 24.8 ppm.

EXAMPLE 23(7S,9aS)-CIS-1-[3-(2-BENZO[d]ISOXAZOL-3-YL-OCTAHYDRO-PYRIDO[1,2-a]PYRAZIN-7-YLMETHOXY-BENZYL]-PYRROLIDIN-3-OL

Final step amine reactant: hydroxypyrrolidine (derived by hydrogenolysisof R-(+)-1-benzyl-3-pyrrolidinol, Aldrich Chem. Co.); final step yield:38% (colorless oil);

¹³C NMR (75 MHz, CDCl₃) δ 164.0, 161.1, 159.3, 140.3, 129.5, 129.2,122.2, 121.0, 116.2, 115.0, 113.2, 110.5, 71.3, 68.7, 63.0, 60.4, 60.3,56.5, 54.2, 53.7, 52.4, 48.3, 35.0, 33.8, 25.2, 24.8 ppm; MS m/z 463(M+1).

EXAMPLE 24(7S,9aS)-CIS-2-BENZO[d]ISOXAZOL-3-YL-7-[3-(2,5-DIMETHYL-[PYRROLIDIN-1-YLMETHYL)-PHENOXYMETHYL-OCTAHYDRO-PYRIDO[1,2-a]PYRAZINE

Final step amine reactant: 2S,5S-dimethylpyrrolidine [P. Beak, S. T.Kerrick, S. Wu, J. Chu, J. Amer. Chem. Soc., 116, 3231-3239 (1994)];final step yield: 19% (colorless oil);

¹³C NMR (75 MHz, CDCl₃) δ 164.0, 161.1, 129.5, 129.0, 128.8, 122.2,121.6, 120.8, 116.2, 115.9, 115.0, 112.6, 110.5, 68.7, 60.4, 59.8, 56.5,55.2, 54.2, 53.7, 51.8, 48.3, 33.8, 31.2, 30.9, 25.2, 24.8, 20.5, 17.0ppm; MS m/z 475 (M+1).

EXAMPLE 25 (7S,9aS)-CIS-2-BENZO[d]ISOXAZOL-3-YL-7-[3-(2,5-DIMETHYL-PYRROLIDIN-1-YLMETHYL)-PHENOXYMETHYL]-OCTAHYDRO-PYRIDOL[1,2-a]PYRAZINE.

Final step amine reactant: 2R,5R-dimethylpyrrolidine [R. P. Short, R. M.Kennedy, S. Masamune, J. Org. Chem., 54, 1755-1756 (1989)]; final stepyield: 19% (colorless oil);

¹³C NMR (75 MHz, CDCl₃) δ 164.0, 161.1, 159.3, 129.5, 129.1, 122.2,121.0, 116.2, 115.2, 110.5, 68.7, 60.5, 56.5, 54.2, 53.7, 51.9, 48.3,33.7, 30.8, 25.2, 24.8, 17.0 ppm; MS m/z 475 (M+1).

EXAMPLE 26(7S,9aS)-CIS-1-[3-(2-BENZO[d]ISOXAZOL-3-YL-OCTAHYDRO-PYRIDO[1.2-a]PYRAZIN-7-YLMETHOXY-BENZYL]-PYRROLIDINE-3,4-DIOL

Final step amine reactant: cis-3,4-dihydroxypyrrolidine (Aldrich Chem.Co.); final step yield: 33% (colorless oil);

¹³C NMR (75 MHz, CDCl₃) δ 163.9, 161.1, 159.3, 139.5, 129.6, 129.3,122.3, 122.2, 121.1, 116.1, 115.2, 113.4, 110.5, 70.5, 68.7, 60.5, 60.3,56.5, 54.2, 53.6, 50.6, 48.2, 33.7, 25.1, 24.7 ppm; MS m/z 479 (M+1).

EXAMPLE 27(7S,9aS)-CIS-1-[3-(2-BENZO[d]ISOXAZOL-3-YL-OCTAHYDRO-PYRIDO[1,2-a]PYRAZIN-7-YLMETHOXY-BENZYL]-PYRROLIDIN-3-OL

Final step amine reactant: hydroxypyrrolidine (derived by hydrogenolysisof S-(−)-1-benzyl-3-pyrrolidinol, Aldrich Chem. Co.); final step yield:64% (colorless oil);

¹³C NMR (75 MHz, CDCl₃) δ 164.0, 161.1, 159.3, 140.4, 129.5, 129.2,122.2, 121.0, 116.2, 115.1, 113.2, 110.5, 71.3, 68.7, 63.0, 60.4, 60.3,56.5, 54.2, 53.7, 53.4, 52.4, 48.3, 35.0, 33.8, 25.2, 24.8 ppm; MS m/z463 (M+1).

EXAMPLE 28(7S,9aS)-CIS-[3-(2-BENZO[d]ISOXAZOL-3-YL-OCTAHYDRO-PYRIDO[1,2-a]PYRAZIN-7-YLMETHOXY-BENZYL]-ISOBUTYL-AMINE

Final step amine reactant: isobutyl amine; final step yield: 38%(colorless oil);

¹³C NMR (75 MHz, CDCl₃) δ 164.0, 161.1, 159.4, 142.3, 129.5, 129.3,122.2, 120.2, 116.2, 114.2, 113.1, 110.5, 68.7, 60.4, 57.5, 56.5, 54.2,54.1, 53.7, 48.3, 33.8, 28.3, 25.2, 24.8, 20.7 ppm; MS m/z 449 (M+1).

EXAMPLE 29(7S,9aS)-CIS-BENZO[d]ISOXAZOL-3-YL-METHYL-{2-[2-METHYL-5-(2-MORPHOLIN-4-YLMETHYL-PHENOXYMETHYL)-PIPERIDIN-1-YL]-ETHYL}-AMINE

Step 1

(7S,9aS)-cis-2-{1-2-(Benzo[d]isoxazol-3-yl-methyl-amino)-ethyl]-6-methyl-piperidin-3-ylmethoxy}-benzonitrile

A reaction mixture consisting of(7S,9aS)-cis-(2-benzo[d]isoxazol-3-yl-OCTAHYDRO-PYRIDO[1,2-a]pyrazin-7-yl)-methanol(1.34 g, 4.66 mmol), 2-cyanophenol (834 mg, 7.0 mmol),triphenylphosphine (1.46 g, 5.60 mmol), and diethylazodicarboxylate (880μl, 5.60 mmol) in tetrahydrofuran (35 ml) was stirred at 50° C. for 4hours. The solvent was removed in vacuo, and the residue was extractedinto a 1 N aqueous sodium hydroxide/methylene chloride biphasic mixture(50 ml of each). The organic phase was then extracted twice with 25 mlportions of saturated aqueous sodium bicarbonate, dried (anhydroussodium sulfate), and concentrated in vacuo to afford an oil (4.57 g).Flash chromatography of the entire sample (silica gel, 47-61 micronmesh; elution with methylene chloride/methanol=97:3 in volume) yieldedthe title compound (1.34 g, 73% yield) as a colorless oil.

TLC R_(f) (silica gel plates; methanol/methylene chloride=4:96 involume; UV detection): 0.64;

¹³C NMR (75 MHz, CDCl₃) δ 164.0, 161.1, 161.0, 134.3, 133.6, 129.5,122.3, 122.2, 120.6, 116.6, 116.2, 112.6, 110.4, 102.0, 69.8, 60.4,56.2, 54.2, 53.7, 48.3, 33.5, 25.1, 24.6 ppm.

Step 2

(7S,9aS-{2-[5-(2-Aminomethyl-phenoxymethyl)-2-methyl-piperidin-1-yl]-ethyl}-benzo[d]isoxazol-3-yl-methyl-amine

To a solution of the Step 1 title compound (1.34 g, 3.4 mmol) inanhydrous tetrahydrofuran (15 ml), a total volume of 10.3 ml (10.3 mmol)of a 1.0M solution of lithium aluminum hydride in tetrahydrofuran wasadded dropwise over 10 minutes. The reaction was stirred, first at 50°C. for 2.5 hours, and then at ambient temperature for 18 hours. With icebath cooling, the reaction was cautiously quenched by dropwise additionof 800 μl of aqueous 1N sodium hydroxide over 20 minutes. After 20minutes of stirring at ambient temperature, solid anhydrous sodiumsulfate was added, and the mixture was filtered through celite. Thefiltrate was concentrated in vacuo, yielding the title compound as acolorless oil (1.0 g, 75% yield).

TLC R_(f) (silica gel plates; elution with methanol/methylenechloride=12:88 in volume; UV detection): 0.17; ¹³C NMR (75 MHz, CD₃OD) δ165.2, 162.4, 158.3, 131.7, 131.1, 129.7, 129.5, 126.0, 123.8, 121.6,117.1, 112.6, 111.1, 69.8, 61.9, 57.4, 55.5, 54.5, 42.8, 35.2, 31.0,26.1, 25.8 ppm.

Step 3

(7S,9aS-cis-Benzo[d]isoxazol-3-yl-methyl-{2-[2-methyl-5-(2-morpholin-4-ylmethyl-phenoxymethyl)-piperidin-1-yl]-ethyl}-amine

A reaction mixture consisting of the title compound of Step 2 (300 mg,0.76 mmol), sodium carbonate (243 mg, 2.3 mmol), and di-2-chloroethylether (112 μl, 0.96 mmol) was stirred at 65° C. for 18 hours. Thesolvent was removed in vacuo, and the residue was extracted into abiphasic 10% dilute aqueous sodium bicarbonate/methylene chloride (20 mlof each) mixture. The aqueous phase was then extracted with two 20 mlportions of methylene chloride. The combined organic extracts were dried(anhydrous sodium sulfate) and concentrated in vacuo to a residue whichwas only partially purified by an initial flash chromatography (12 gsilica gel, 47-61 micron mesh; elution with methanol/methylenechloride=4:96 in volume). The resulting 115 mg of solid semi-purifiedproduct was treated on a second flash chromatography column (6 g silicagel, 47-61 micron mesh; elution with methanol/methylene chloride=2:98 involume) to afford the title compound (40 mg, 11% yield) as an amorphouscolorless solid.

MS m/z 463 (M+1); ¹³C NMR (75 MHz, CDCl₃) δ 164.0, 162.0, 157.5, 130.6,129.5, 128.2, 126.0, 122.2 (2), 120.2, 111.7, 110.5, 68.8, 67.1, 60.4,56.6, 54.3, 53.7, 53.6, 48.3, 33.9, 25.2, 24.8 ppm.

EXAMPLE 30(7S,9aS)-CIS-2-BENZO[d]ISOXAZOL-3-YL-7-(2-PYRROLIDIN-1-YLMETHYL-PHENOXYMETHYL)-OCTAHYDRO-PYRIDO[1,2-a]PYRAZINE

To a solution of the title compound of Example 26, Step 2 (300 mg, 0.76mmol) in N,N-dimethylformamide (3.5 ml), sodium carbonate (243 mg, 2.3mmol) and 1,4-dibromobutane (100 μl, 0.84 mmol) were added, and thereaction mixture was stirred at 80° C. for 18 hours. The solvent wasremoved in vacuo, and the residue was extracted into a 5% dilute aqueoussodium carbonate/methylene chloride (15 ml of each) biphasic mixture.The aqueous phase was then extracted with three 10 ml portions of freshmethylene chloride. The combined organic extracts were dried (anhydroussodium sulfate), and concentrated in vacuo, yielding an oil (300 mg).Flash chromatography of the entire sample (silica gel, 47-61 micronmesh; elution with methanol/methylene chloride=1:9 in volume) affordedthe title product (300 mg, 41% yield) as a colorless oil.

¹³C NMR (75 MHz, CDCl₃) δ 164.0, 161.1, 157.5, 133.4, 131.7, 129.5,122.3, 122.1, 121.2, 117.3, 116.1, 112.3, 110.4, 69.4, 60.3, 56.5, 54.2,53.6, 52.2, 51.1, 48.2, 33.7, 25.0, 24.9, 23.1 ppm; MS m/z 447 (M+1).

EXAMPLE 31(7S,9aS)-CIS-2-BENZO[d]ISOXAZOL-3-YL-7-(4-MORPHOLIN-4-YLMETHYL-PHENOXYMETHYL)-OCTAHYDRO-PYRIDO[1,2-a]PYRAZINE

Step 1

(7S,9aS)-cis-4-(2-Benzo[d]isoxazol-3-yl-octahydro-pyrido[1,2-a]pyrazin-7-ylmethoxy)-benzonitrile

To a solution of(7S,9aS)-cis-(2-benzo[d]isoxazol-3-yl-octahydro-pyrido[1,2-a]pyrazin-7-yl)-methanol(1.33 g, 4.6 mmol), 4-cyanophenol (828 mg, 6.9 mmol), triphenylphosphine(1.46 g, 5.6 mmol) and diethylazodicarboxylate (947 μl, 5.6 mmol) wereadded, and the resulting mixture was stirred at 50° C. for 5 hours. Thesolvent was removed in vacuo, and the residue was extracted into a 10%aqueous sodium bicarbonate/methylene chloride (30 ml of each) mixture.The aqueous phase was extracted with three 10 ml portions of freshmethylene chloride. The combined organic extracts were dried (anhydroussodium sulfate), and concentrated in vacuo to an oil. Flashchromatography (silica gel, 47-61 micron mesh; elution withmethanol/methylene chloride=1:99 in volume) afforded the title compound(quantitative yield) as an amber oil.

MS m/z 389 (M+1).

Step 2

(7S,9aS)-cis-4-(2-Benzo[d]isoxazol-3-yl-octahydro-pyrido-1,2-a]pyrazin-7-ylmethoxy)-benzylamine

To a solution of the title compound from the previous step (2.9 g, 4.6mmol) in anhydrous tetrahydrofuran (16 ml), a 1.0M solution of lithiumaluminum hydride in tetrahydrofuran (13.8 ml, 13.8 mmol) was addeddropwise over several minutes. The reaction mixture was then stirred at50° C. for 4 hours. With ice bath cooling, the reaction was thenquenched by dropwise addition of 1N aqueous sodium hydroxide (1 ml) over20 minutes. After stirring at ambient temperature for 1 hour, anhydroussodium sulfate was added. The mixture was filtered, and the filtrate wasconcentrated in vacuo yielding a viscous oil. The crude amine productwas further purified by hydrochloride salt formation as follows: Theentire sample was dissolved in ethanol/ethyl acetate (10 ml of each). Anether solution (20 ml) saturated with anhydrous hydrogen chloride wasadded, yielding the amine bis-hydrochloride salt as a colorlessamorphous precipitate, which was filtered and dried in vacuo. The freebase was liberated by dissolution of the entire sample in a 10% aqueoussodium carbonate/methylene chloride (50 ml of each) mixture. The aqueousphase was then extracted with three 5 ml portions of fresh methylenechloride. The combined organic extracts were dried (anhydrous sodiumsulfate) and concentrated in vacuo to afford the title compound (730 mg)as a colorless oil.

¹³C NMR (75 MHz, CD₃OD) δ 165.2, 162.4, 160.8, 133.2, 133.0, 131.2,130.9, 130.0, 129.6, 123.8, 117.1, 116.0, 111.1, 69.8, 61.9, 57.2, 55.4,54.5, 44.7, 35.1, 26.0, 25.7 ppm; MS m/z 393 (M+1).

Step 3

(7S,9aS)-cis-2-benzo[d]isoxazol-3-yl-7-(4-morpholin-4-ylmethyl-phenoxymethyl)octahydro-pyrido[1,2-a]pyrazine

To a solution of the title compound from Step 2 (175 mg, 0.45 mmol) inN,N-dimethylformamide (20 ml), sodium carbonate (142 mg, 1.33 mmol) and2-chloroethyl ether (72 μl, 0.50 mmol) were added, and the reactionmixture was stirred at 85° C. for 18 hours. The solvent was then removedin vacuo, and the residue was extracted with a water/methylene chloride(15 ml of each) biphasic mixture. The aqueous phase was extracted withthree 10 ml portions of fresh methylene chloride. The combined organicextract were dried (anhydrous sodium sulfate), and concentrated invacuo, yielding an oil (170 mg). Flash chromatography of the entiresample (silica gel, 47-61 micron mesh; elution with methanol/methylenechloride=2.98 in volume) afforded the title compound (19 mg, 9% yield)as an oil.

¹³C NMR (75 MHz, CDCl₃) δ 164.0, 161.0, 158.6, 130.4, 129.5, 122.2,116.0, 114.4, 110.5, 68.8, 67.02, 62.9, 60.4, 56.5, 54.2, 53.7, 53.5,48.3, 33.7, 25.2, 24.8 ppm; MS m/z 463 (M+1).

EXAMPLE 32(7S,9aS)-CIS-2-BENZO[d]ISOXAZOL-3-YL-7-(4-PYRROLIDIN-1-YLMETHYL-PHENOXYMETHYL)-OCTAHYDRO-PYRIDOL[1,2-a]PYRAZINE

To a solution of the title compound of Example 31, Step 2 (200 mg, 0.51mmol) in N,N-dimethylformamide (2.5 ml), sodium carbonate (162 mg, 1.53mmol) and 1,4-dibromobutane (67 μl, 0.56 mmol) were added, and thereaction mixture was stirred at 85° C. for 18 hours. The solvent wasremoved in vacuo, and the residue was extracted into a 5% dilute aqueoussodium carbonate/methylene chloride (15 ml of each) biphasic mixture.The aqueous phase was extracted with three 10 ml portions of freshmethylene chloride. The combined organic extracts were dried (anhydroussodium sulfate) and concentrated in vacuo, yielding an oil (220 mg).Flash chromatography of the entire sample (silica gel, 47-61 micronmesh; elution with methanol/methylene chloride=6:94 in volume) affordedthe title compound (22 mg, 10% yield) as an oil.

¹³C NMR (75 MHz, CDCl₃) δ 164.0, 161.0, 160.4, 135.0, 132.2, 129.5,122.3, 122.2, 116.3, 115.3, 110.4, 68.9, 60.4, 57.8, 56.3, 54.2, 53.6,52.6, 48.3, 33.5, 25.1, 24.7, 23.1 ppm; MS m/z447 (M+1).

EXAMPLE 33(7R,9aS)-TRANS-2-(7-FLUORO-BENZO[d]ISOXAZOL-3-YL)-7-(3-PYRROLIDIN-1-YLMETHYL-PHENOXYMETHYL)-OCTAHYDRO-PYRIDO[1,2-a]PYRAZINE

Step 1

(7R,9aS)-trans-2,3-Difluoro-N′-hydroxy-N-methyl-N-{2-[2-methyl-5-(2-pyrrolidin-1-ylmethyl-phenoxymethyl)-piperidin-1-yl]-ethyl}-benzamidine

Reactant 2,3-difluorobenzohydroximinoyl chloride was prepared in situ asfollows: A steady stream of chlorine gas was passed for 30 minutesthrough a dry ice-acetone bath chilled, well-stirred, partial solutionof 2,3-difluoro-benzaldehyde oxime (400 mg, 2.55 mmol) in chloroform(2.62 ml). Excess chlorine was removed by a 10 minute purge withnitrogen. A total of 254 μl (1.80 mmol) of triethylamine was then addeddropwise. The reaction mixture was filtered, to afford (in the filtrate)a chloroform solution of the iminoyl chloride reactant. To an ambienttemperature solution of the title compound of Example 5, Step 4 (1.51 g,3.76 mmol) and 1,8-diazabicyclo[5.4.0]-undec-7-ene (1.13 ml, 7.52 mmol)in chloroform (3.2 ml), the entire aforedescribed solution of2,4-difluorobenzohydroximinoyl chloride was added dropwise (exotherm).After 20 minutes of stirring, the reaction was quenched by addition of20 ml of 10% dilute aqueous sodium bicarbonate. The reaction mixture wasthen extracted with three successive 20 ml portions of methylenechloride. The combined organic extracts were dried (anhydrous sodiumsulfate) and concentrated in vacuo to an oil (1.5 g). Flashchromatography of the entire sample (silica gel, 47-61 micron mesh;elution with methanol/methylene chloride=6:94 in volume) afforded thetwo (syn and anti) oxime isomers of the title compound as amorphoussolids.

TLC R_(f) of less polar isomer (246 mg, 14% yield; silica gel plates;elution with methanol/methylene chloride=6:94 in volume; UV detection:0.39.

MS m/z 485 (M+1).

TLC of more polar isomer (164 mg, 9% yield; identical TLC conditions):0.33; MS m/z 485 (M+1).

Step 2

(7R,9aS)-trans-2-(7-Fluoro-benzo[d]isoxazol-3-yl)-7-(3-pyrrolidin-1-ylmethyl-phenoxymethyl)-octahydro-pyrido[1,2-a]pyrazine

To a well-stirred partial solution of the entire product sample fromStep 1 (combined oxime isomers; 410 mg, 0.85 mmol) in tetrahydrofuran,sodium hydride (38 mg of a 60% mineral oil dispersion, 0.96 mmol ofsodium hydride) was added portionwise over several minutes. Anhydroustoluene (2.22 ml) was added, and the reaction was heated at 90° C. for18 hours. At ambient temperature, first ethanol (178 μl) and then aceticacid (33 μl) were added. After stirring for 20 minutes, water was added,and the pH was adjusted to 10 by dropwise addition of 30% aqueousammonium hydroxide. The mixture was then extracted with three 20 mlportions of methylene chloride. The combined organic extracts were dried(anhydrous sodium sulfate) and concentrated in vacuo to afford an oil(470 mg). Flash chromatography (silica gel, 47-61 micron mesh; elutinginitial with methanol/methylene chloride=6:94 in volume, increasing themethanol concentration to a final 12:88 volume ratio) afforded the titlecompound (180 mg, 46% yield) as a colorless amorphous solid.

MS m/z 465 (M+1).

EXAMPLE 34(7R,9aS)-TRANS-2-(6-FLUORO-BENZO[d]ISOXAZOL-3-YL)-7-(3-PYRROLIDIN-1-YLMETHYL-PHENOXYMETHYL)-OCTAHYDRO-PYRIDO[1,2-a]PYRAZINE

Step 1

(7R,9aS)-trans-2,4-Difluoro-N′-hydroxy-N-methyl-N-{2-[2-methyl-5-(3-pyrrolidin-1-ylmethyl-Phenoxymethyl)-piperidin-1-yl]-ethyl}-benzamidine

Reactant 2,4-difluorobenzohydroximinoyl chloride was prepared in situ in2.2 ml of chloroform from 2,4-difluoro-benzaldehyde oxime (325 mg, 2.1mmol) by the procedure of Example 33, Step 1 (207 μl, 1.5 mmol oftriethylamine was used). As before, excess chlorine was removed bynitrogen purge. As in the previous example, the solution of2,4-difluorobenzohydroximinoyl chloride was added dropwise to a solutionof the title compound from Example 5/Step 4 (1.22 g, 3.1 mmol) and1,8-diazabicyclo[5.4.0]-undec-7-ene (927 μl, 6.2 mmol) in chloroform(2.6 ml). Work-up as in the previous example afforded 1.12 g of an oil.Flash chromatography of the entire sample (silica gel, 47-61 micronmesh; elution with methanol/methylene chloride=1:9 in volume) affordedthe two isomeric oximes as amorphous solids.

TLC R_(f) of less polar isomer (126 mg, 12% yield; silica gel plates;elution with methanol/methylene chloride 1:9 in volume): 0.38;

MS m/z 485 (M+1).

TLC R_(f) of more polar isomer (218 mg, 21% yield; identical TLCconditions): 0.29;

MS m/z 485 (M+1).

Step 2

(7R,9aS)-trans-2-(6-Fluoro-benzo[d]isoxazol-3-yl)-7-(3-pyrrolidin-1-ylmethyl-phenoxymethyl)-octahydro-pyrido[1,2-a]pyrazine

Utilizing the entire product sample (combined oxime isomers) from Step 1[and the following reagent/solvents: sodium hydride (30 mg of 60%mineral oil dispersion, 0.76 mmol of sodium hydride), anhydroustetrahydrofuran (0.60 ml), and anhydrous toluene (1.75)], the titlecompound (103 mg, 33% yield as a colorless oil) was prepared by thegeneral procedure of Example 33, Step 2. (Flash chromatography in thefinal purification: silica gel 47-61 micron mesh; initial elution withmethanol/methylene chloride=6:94 in volume, increase methanolconcentration to a final 1:9 volume ratio).

MS m/z 465 (M+1); ¹³C NMR (75 MHz, CDCl₃) δ 162.0, 159.1, 129.2, 123.2,123.0, 121.4, 114.9, 113.0, 111.5, 111.2, 97.9, 97.5, 70.9, 60.6, 60.1,58.8, 54.2, 54.1, 53.7, 48.3, 36.4, 29.0, 26.9, 23.4 ppm.

EXAMPLE 35(7R,9aS)-TRANS-2-(6,7-DIFLUORO-BENZO[d]ISOXAZOL-3-YL)-7-(3-PYRROLIDIN-1-YLMETHYL-PHENOXYMETHYL)-OCTAHYDRO-PYRIDO[1,2-a]PYRAZINE

Step 1

(7R,9aS)-2,3,4-Trifluoro-N′-hydroxy-N-methyl-N-{2-[2-methyl-5-(3-pyrrolidin-1-ylmethyl-phenoxymetyyl)-piperidin-1-yl]-ethyl}-benzamidine

By the general method in Step 1 of Examples 33 and 34, and utilizing2,3,4-trifluorobenzaldehyde oxime (89 mg, 0.51 mmol) as startingmaterial, a chloroform (530 μl) of 2,3,4-trifluorobenzohydroximinoylchloride was generated in situ. By the general Step 2 method of Examples33 and 34, the entire sample was reacted with the Example 5/Step 4 titlecompound (300 mg, 0.75 mmol) in chloroform (51 μl) in the presence of1,8-diazabicyclo[5.4.0]-undec-7-ene (223 μl, 1.5 mmol). Work-up as citedin the two previous examples and flash chromatography (silica gel, 47-61micron mesh; elution with methanol/methylene chloride 12:88 in volume)afforded a single oxime isomer (105 mg, 41% yield) as an oil.

TLC R_(f) (silica gel plates; elution with methanol/methylenechloride=12:88 in volume; UV detection): 0.66.

MS m/z 503 (M+1); ¹³C NMR (75 MHz, CDCl₃) δ 159.1, 148.0, 140.2, 138.1,129.1, 125.4, 121.4, 120.0 (2), 115.0, 113.2, 112.1, 112.0, 70.9, 61.1,60.6, 58.7, 55.0, 54.1, 53.2, 47.8, 36.3, 28.7, 26.9, 23.4 ppm.

Step 2

(7R,9aS-trans-2-(6,7-Difluoro-benzo[d]isoxazol-3-yl)-7-(3-pyrrolidin-1-ylmethyl-phenoxymethyl)-octahydro-pyrido[1,2-a]pyrazine

Utilizing the entire product sample from Step 1 [and the followingreagents/solvents: sodium hydride (9.4 mg of 60% mineral oil dispersion,0.24 mol of sodium hydride), anhydrous tetrahydrofuran (0.5 ml), andanhydrous toluene (0.6 ml)], the title compound (24 mg, 25% yield as acolorless amorphous solid) was prepared by the general procedure of Step2, Examples 34 and 35. (Flash chromatography in the final purification:silica gel, 47-61 micron mesh; elution with methanol/methylenechloride=8:92 in volume).

TLC R_(f) (silica gel plates, elution with methanol/methylenechloride=8:92 in volume;

UV detection): 0.28;

MS m/z 483 (M+1).

EXAMPLE 36(7R,9aS-TRANS-2-(5-FLUORO-BENZO[d]ISOXAZOL-3-YL)-7-(3-PYRROLIDIN-1-YLMETHYL-PHENOXYMETHYL)-OCTAHYDRO-PYRIDO[1,2-a]PYRAZINE

Step 1

(7S,9aS)-cis-7-hydroxymethyl-2,3,4,6,7,8,9,9a-octahydro-1H-pyrido[1,2-a]-pyrazine-bis-hydrochloride(cf. F. J. Urban, European Patent Application EP 646116, published Apr.5, 1995).

To a well-stirred ice bath chilled slurry of(7S,9aS)-cis-7-hydroxymethyl-2-tert-butoxycarbonyl)-2,3,4,6,7,8,9,9a-octahydro-1H-pyrido[1,2-a]pyrazine(150 g, 0.56 mol) in isopropyl ether (750 ml), a solution of anhydroushydrochloric acid (61 g) in isopropyl ether (900 ml) was added in aslow, steady stream while maintaining the temperature below 10° C. Afterstirring the mixture at ambient temperature for 18 hours, the colorlesssolid was filtered and then dried in vacuo to afford the title compoundbis-hydrochloride salt (quantitative yield).

Step 2

(7S,9aS)-cis-[2-(5-fluoro-benzo[d]isoxazol-3-yl)-octahydro-pyridol[1,2-a]pyrazin-7-yl]-methanol

To a stirred slurry of the (bis-hydrochloride salt) product of Step 1(5.70 g, 27.6 mmol) and 3-chloro-5-fluoro-benzo[d]isoxazole (5.83 g,33.9 mmol) in pyridine (17 ml), 1,8-diazabicyclo[5.4.0]undec-7-ene (13.6ml, 90 mmol) was added, and the resulting reaction mixture was heated at100° C. for 18 hours. At ambient temperature the reaction mixture wasvigorously mixed with a 10% aqueous sodium bicarbonate/methylenechloride (100 ml of each) biphasic mixture. The separated aqueous phasewas extracted with three 50 ml portions of fresh methylene chloride. Thecombined organic extracts were, in turn, extracted with an equal volumeof water, and then dried (anhydrous sodium sulfate) and concentrated invacuo to an oil. Three successive triturations of the entire sample with50 ml portions of a 1:4 mixture of ethyl acetate:hexanes was followed bycareful removal of the supernatant liquid with a pipet. Finally, tracesof residual solvent were removed in vacuo to afford the title compound(3.13 g, 37% yield) as a viscous amber oil.

¹³C NMR (75 MHz, CDCl₃) δ 160, 118.2, 117.9, 111.4, 111.3, 107.1, 67.9,60.1, 58.3, 54.1, 53.7, 48.3, 34.3, 27.0, 26.4 ppm; MS m/z 306 (M+1).

Step 3

(7S,9aS)-cis-2-(5-fluoro-benzo[d]isoxazol-3-yl)-octahydro-pyridol[1,2-a]pyrazine-7-carboxaldehyde

To a well stirred ice bath-chilled solution of the title compound of theprevious step (2.0 g, 6.5 mmol) and diisopropylethylamine (4.62 ml, 26mmol) in methylene chloride (50 ml), a slurry of pyridine-sulfurtrioxide complex (3.1 g, 1.95 mmol) in dimethylsulfoxide (1.20 ml) wasadded portionwise at a rate that maintained the temperature just below10° C. The reaction mixture was stirred at ambient temperature for 18hours. Water (100 ml) was added and the biphasic mixture was vigorouslystirred. The separated aqueous phase was extracted with three 50 mlportions of fresh methylene chloride. The extracts (four) were combinedand, in turn, extracted with three 40 ml portions of aqueous 1Nhydrochloric acid. The pH of the separated acidic aqueous phase waselevated to 10 by addition of aqueous 3N sodium hydroxide, causingprecipitation of a colorless fine solid, which was isolated byfiltration. The entire filter cake was dissolved in methylene chloride(350 ml), and the resulting solution was dried (anhydrous sodiumsulfate). Solvent removal in vacuo afforded an oil (1.8 g). Flashchromatography of the entire sample (silica gel, 47-61 micron mesh;elution with methanol/methylene chloride=3:97 in volume) afforded thetitle compound (750 mg, 38% yield) as a colorless amorphous solid.

MS m/z 304 (M+1).

Thin Layer Chromatography (TLC) R_(f) (Analtech Uniplates: silica gelGF, 250 micron mesh; elution with methanol/methylene chloride=4:96 involume; UV detection): 0.46.

Step 4

(7R,9aS)-trans-2-(5-fluoro-benzo[d]isoxazol-3-yl)-octahydro-pyridol[1,2-a]pyrazin-7-carboxaldehyde

To a solution of the title compound from the previous step (750 mg, 2.47mmol) in methanol (15 ml), solid potassium carbonate (83 mg, 0.6 mmol)was added, and the resulting mixture was vigorously stirred at ambienttemperature for 18 hours (thus effecting a 7S to 7R site epimerizationwith the Step 3 title compound). The solvent was removed in vacuo, andthe residue was extracted into a water/methylene chloride biphasicmixture (50 ml of each). The separated aqueous phase was extracted withthree 35 ml portions of fresh methylene chloride.

The combined organic extracts were dried (anhydrous sodium sulfate) andconcentrated in vacuo to afford the title compound (602 mg, 80% yield)as an amorphous solid, used in the next step without furtherpurification.

MS m/z 304 (M+1);

TLC R_(f) (identical conditions to those reported in the previous step):0.25.

Step 5

(7R,9aS)-trans-[2-(5-fluoro-benzo[d]isoxazol-3-yl)-octahydro-pyridol[1,2-a]pyrazin-7-yl]-methanol

To a well-stirred, ambient temperature solution of the title compoundfrom the previous step (602 mg, 1.98 mmol) in methanol (15 ml), solidsodium borohydride (75 mg, 1.98 mmol) was added portionwise over 5minutes. The reaction mixture was stirred for 18 hours at ambienttemperature, and then filtered. The filtrate was concentrated in vacuo,and the residue was extracted into a water/methylene chloride (30 ml ofeach) biphasic mixture. The separate aqueous phase was extracted withthree 35 ml portions of fresh methylene chloride. The combined organicextracts were dried (anhydrous sodium sulfate) and then concentrated invacuo to afford the title compound (260 mg, 43% yield) as a colorlessamorphous solid, identical in all respects to the title compound productof Example 8, Step 1.

Step 6

(7R,9aS)-trans-methanesulfonicAcid-2-(5-fluoro-benzo[d]isoxazol-3-yl)-octahydro-pyridol[1,2-a]pyrazin-7-yl-ester

To a well-stirred ice bath-chilled solution of the title compoundproduct of the previous step (250 mg, 0.82 mmol) and triethylamine (143μl, 1.03 mmol) in methylene chloride (5 ml), methanesulfonyl chloride(70 μl, 0.90 mmol) was added. The reaction mixture was stirred (5° C.)for 10 minutes. The ice cooling bath was removed, and the reaction wasallowed to warm for 10 minutes before quenching by vigorous mixing witha 10% aqueous sodium bicarbonate/methylene chloride (30 ml of each)biphasic mixture. The separated aqueous phase was then extracted withthree 15 ml portions of fresh methylene chloride. The combined organicextracts were dried (anhydrous sodium sulfate) and concentrated in vacuoto afford the title compound (300 mg, 95% yield) as an amorphous solid.

MS m/z 384 (M+1).

Step 7

(7R,9aS)-trans-2-(5-fluoro-benzo[d]isoxazol-3-yl)-7-(3-pyrrolidin-1-ylmethyl-phenoxymethyl)-octahydro-pyrido[1,2-a]pyrazine

To a solution of 3-(1-pyrrolidinylmethyl)-phenol [Eur. J. Med. Chem.Chim. Ther. 20, 6, 571-574 (1985); 139 mg, 0.78 mmol] in anhydrousN-methylpyrrolidinone (1.0 ml), sodium hydride (38 mg of a 60% mineraloil dispersion, 0.95 mmol of sodium hydride) was added portionwise overseveral minutes. After stirring for 10 minutes at ambient temperature,the reaction mixture was heated at 65° C. for 15 minutes. A solution ofthe (mesylate) title compound product from the previous step (300 mg,0.78 mmol) in anhydrous N-methyl-pyrrolidinone (2.5 ml) was added, andthe stirred reaction mixture was heated at 65° C. for 18 hours. Atambient temperature, the reaction was quenched by addition/vigorousmixing with water (50 ml). The separated aqueous phase was extractedwith three 5 ml portions of methylene chloride. The combined organicextracts were, in turn, extracted with two 30 ml portions of water, andthen dried (anhydrous sodium sulfate). Concentration in vacuo yielded anoil (627 mg). Three successive triturations of the entire sample with 5ml portions of hexanes with careful pipet removal of supenatant liquidafter each trituration, yielded the title compound as an amorphouscolorless solid (312 mg, 86% yield), identical in all respects to the(free base) title compound of Example 5, Step 5.

EXAMPLE 37(7R,9aS)-TRANS-3-{3-[2-(5-FLUORO-BENZO[d]ISOXAZOL-3-YL)-OCTAHYDRO-PYRIDO[1,2-a]PYRAZIN-7-YLMETHOXY]-BENZYL}-3-AZA-BICYCLO[3.2.2]NONANE

Step 1

(7R,9aS)-trans-7-[3-(3-aza-bicyclo[3.2.2]non-3-ylmethyl)-phenoxymethyl]-octahydro-pyrido[1,2-a]pyrazine-2-carboxylicacid tert-butyl ester

To an ice bath-chilled and stirred solution of the title compound ofExample 5, Step 2, 600 mg, 1.6 mmol) and triethylamine (278 μl, 1.99mmol) in anhydrous methylene chloride, methanesulfonyl chloride (135 μl,1.75 mmol) was added, and the resulting reaction mixture was stirred(5-10° C.) for 20 minutes before quenching by addition of 10% aqueoussodium bicarbonate/methylene chloride (20 ml of each). The aqueous phasewas then extracted with three 20 ml portions of fresh methylenechloride. The combined organic extracts were dried (anhydrous sodiumsulfate) and concentrated in vacuo to a residue which was dissolved inacetonitrile (10 ml). 3-Azabicyclo[3.2.2]-nonane (Aldrich Chemical Co.,597 mg, 4.78 mmol) was added, and the reaction solution was heated at50° C. for 18 hours. The solvent was removed in vacuo, and the residuewas extracted into a 10% aqueous sodium bicarbonate/methylene chloridemixture (25 ml of each). The separated aqueous phase was re-extractedwith three 20 ml portions of fresh methylene chloride. The combinedorganic extracts were dried (anhydrous sodium sulfate) and concentratedin vacuo, affording an oil (940 mg). Flash chromatography of the entiresample (silica gel, 47-61 micron mesh; elution with methylenechloride/methanol=96:4 in volume) afforded the title compound as acolorless amorphous solid (320 mg, 42% yield).

¹³C NMR (75 MHz, CDCl₃) δ 158.8, 154.5, 142.0, 128.9, 120.8, 114.3,112.6, 79.6, 70.6, 62.7, 62.5, 60.7, 58.7, 54.7, 36.2, 30.4, 28.6, 28.3,26.8, 25.8, 14.4 ppm; MS m/z 484 (M+1).

Step 2

(7R,9aS)-trans-3[octahydro-pyrido[1,2-a]pyrazin-7-ylmethoxy)-benzyl]-3-aza-bicyclo[3.2.2]nonanebis-hydrochloride

The title compound from the previous step (320 mg, 0.66 mmol) wasdissolved in chloroform 5 ml. A diethyl ether (saturated) solution (6ml) of anhydrous hydrochloric acid was added, and the resulting solutionwas stirred at ambient temperature for 18 hours. The solvent was removedto afford the title compound (bis-hydrochloride salt) as a colorlessamorphous foam (quantitative yield).

¹³C NMR (75 MHz, CD₃OD) δ 160.5, 132.1, 131.4, 125.5, 118.7, 117.7,70.4, 62.3, 60.5, 57.3, 51.0, 46.3, 42.0, 35.5, 29.5, 27.0 (2), 25.4,22.5 ppm.

Step 3

(7R,9aS)-trans-3-{3-[2-(5-fluoro-benzo[d]isoxazol-3-yl)-octahydro-pyrido[1,2-a]pyrazin-7-ylmethoxy]-benzyl}-3-aza-bicyclo[3.2.2]nonane

A reaction mixture consisting of the title compound from the previousstep (410 mg, 0.90 mmol), 3-chloro-5-fluoro-1,2-benzo[d]isoxazole (201mg, 1.17 mmol), and 1,8-diazabicyclo[5.4.0]-undec-7-ene (442 μl, 2.92mmol) in anhydrous pyridine (400 μl) was heated at 90° C. for 18 hours.The reaction mixture was then well-mixed with a 10% aqueous sodiumbicarbonate/methylene chloride mixture (20 ml of each). The separatedaqueous phase was re-extracted with three 15 ml portions of methylenechloride. The combined organic extracts were dried (anhydrous sodiumsulfate) and concentrated in vacuo to an oil (415 mg). Flashchromatography (silica gel, 47-61 micron mesh; elution withmethanol/methylene chloride=3:97 in volume) afforded the title compound(69 mg, 15% yield) as a colorless amorphous solid.

MS m/z 519 (M+1).

EXAMPLE 38(7R,9aS)-TRANS-2-(5-FLUORO-BENZO[d]ISOXAZOL-3-YL)-7-[3-CIS-OCTAHYDRO-ISOINDOL-2-YLMETHYL)-PHENOXYMETHYL]-OCTAHYDRO-PYRIDO[1.2-a]PYRAZINE

Step 1

(7R,9aS)-trans-7-[3-octahydro-isoindol-2-ylmethyl)-phenoxymethyl]-octahydro-pyrido[1.2-a]pyrazine-2-carboxylicacid tert-butyl ester

To an ice bath chilled and stirred solution of the title compound ofExample 5, Step 2 (600 mg, 1.6 mmol) and triethylamine (279 μl, 2.0mmol) in anhydrous methylene chloride (10 ml), methane sulfonyl chloride(135 μl, 1.75 mmol) was added. The resulting solution was stirred atambient temperature for 20 minutes prior to quenching by addition (withvigorous stirring) of a 10% aqueous sodium carbonate (20 ml). Theseparated aqueous phase was extracted with three 25 ml portions of freshmethylene chloride. The combined organic extracts were dried (anhydroussodium sulfate) and concentrated in vacuo to afford a residue which wasdissolved in acetonitrile (10 ml). Cis-octahydroisoindole [Dunet, etal., Bull. Soc. Chim. Fr., 906-909 (1956); 550 mg, 4.4 mmol] was added,and the reaction solution was heated at 55° C. for 18 hours. Withvigorous stirring the reaction was quenched by addition of a 10% aqueoussodium bicarbonate and methylene chloride (25 ml of each). The separatedaqueous phase was extracted with three equal volume portions of freshmethylene chloride. The combined organic extracts were dried (anhydroussodium sulfate) and concentrated in vacuo, yielding an oil (870 mg).Flash chromatography (silica gel, 47-61 micro mesh; elution withmethanol/methylene chloride=7:93 in volume) afforded the title compound(290 mg, 38% yield) as a colorless oil.

MS m/z 484 (M+1).

Step 2

(7R,9aS)-trans-7-[3-cis-octahydro-isoindol-2-ylmethyl)-phenoxymethyl]-octahydro-pyrido[1,2-a]pyrazine-bis-hydrochloride

To a solution of the title compound (260 mg) from the previous step inchloroform (6 ml) a diethyl ether (saturated solution, 6 ml) ofanhydrous hydrochloric acid was added. The reaction mixture was stirredfor 18 hours at ambient temperature. Solvent/excess hydrochloric acidremoval in vacuo afford the title compound as a light tan amorphous foam(quantitative yield).

MS m/z 384 (M+1, free base).

Step 3

(7R,9aS)-trans-2-(5-fluoro-benzo[d]isoxazol-3-yl)-7-[3-cis-octahydro-isoindol-2-ylmethyl)-phenoxymethyl]-octahydro-pyrido[1,2-a]pyrazine

The free base of the title compound from the previous step was formed bydissolution of the entire bis-hydrochloride sample into a 50% aqueoussodium bicarbonate/methylene chloride biphasic mixture (20 ml of each)and in vacuo solvent removal/drying of the separated organic phase. Areaction solution of the liberated free base (253 mg, 0.55 mmol),3-chloro-5-fluoro-benzo[d]isoxazole (123 mg, 0.72 mmol), and1,8-diazabicyclo[5.4.0]-undec-7-ene (271 μl, 1.79 mmol) in anhydrouspyridine (250 μl) was heated at 90° C. for 18 hours. The solvent wasremoved in vacuo, and the residue was dissolved in a 10% aqueous sodiumbicarbonate/methylene chloride (40 ml of each) biphasic mixture. Theseparated organic phase was extracted with three 20 ml portions of freshmethylene chloride. The combined organic extracts were dried (anhydroussodium sulfate) and concentrated in vacuo, yielding an oil (370 mg).Flash chromatography of the entire sample (silica gel, 47-61 micro mesh;elution with methanol/methylene chloride=8:92 in volume), followed bypulping in 4 ml of ethyl acetate, afforded the title compound as acolorless amorphous solid (74 mg, 26% yield).

MS m/z 519 (M+1).

EXAMPLE 39(7R,9aS)-TRANS-2-(5-FLUORO-BENZO[d]ISOXAZOL-3-YL)-7-[3-PYRROLIDIN-1-YLMETHYL-PHENOXYMETHYL)-OCTAHYDROPYRIDO[1,2-a]PYRAZINE

Step 1

(7R,9aS)-trans-(2,5-Difluoro-phenyl)-[7-(3-pyrrolidin-1-ylmethyl-phenoxymethyl)-octahydro-pyrido[1,2-a]pyrazin-2-yl]-methanoneOxime

Using the procedure of Step 1 of Examples 34 and 35, and using2,5-difluorobenzaldehyde oxime (79 mg, 0.50 mmol) as the startingmaterial, and triethylamine (49 μl, 0.35 mmol) as a base, and chloridegas as a reactant, a chloroform solution (529 μl) of2,5-difluorobenzohydroximinoyl chloride was generated in situ, and thenreacted with the title compound from Example 5, Step 4 (300 mg, 0.75mmol) by the method of Step 2, Examples 34 and 35,1,8-Diazabicyclo[5.4.0]-undec-7-ene (223 μl, 1.5 mmol) and chloroform(635 μl) were used, respectively, as the base and reaction solvent, andthe reaction was conducted for 18 hours at ambient temperature. Work upof the reaction mixture was conducted as indicated in Examples 33, 34and 35, and flash chromatography (silica gel, 47-61 micro mesh; elutioninitially with methanol/methylene chloride=8:92 in volume, increasingelution solvent polarity during the process to a finalmethanol/methylene chloride/concentrated aqueous ammoniumhydroxide=20:79:1 mixture in volume) afforded the title compound (syn,anti-oxime mixture) as a colorless oil (90 mg, 37% yield).

MS m/z 485 (M+1).

Step 2

(7R,9as)-trans-2-(5-fluoro-benzo[d]isoxazol-3-yl)-7-[3-pyrrolidin-1-ylmethyl-phenoxymethyl)-octahydro-pyrido[1,2-a]pyrazine

The entire sample product from Step 1 (90 mg, 0.19 mmol) was stirred inanhydrous tetrahydrofuran (150 μl). Sodium hydride (17.8 mg of a 60%sodium hydride mineral oil dispersion; 44 mmol of sodium hydride),toluene (475 μl), and anhydrous dimethylformamide (500 μl) were added,and the reaction mixture was heated at 85° C. for 18 hours. Twoadditional portions of sodium hydride (each 8.9 mg of 60% sodium hydridemineral oil dispersion; each 22 mmol of sodium hydride) were added atthe beginning and after two hours of a final four hour 85° C. reactionheating period. Ethanol (39 μl) and acetic acid (7.3 μl) were added,with stirring, to the cooled mixture. Five minutes thereafter, water (4ml) was carefully added, and the resulting mixture was extracted withthree 10 ml portions of methylene chloride. The combined organicextracts were dried (anhydrous sodium sulfate) and concentrated in vacuoto an oil (200 mg). Flash chromatography of the entire sample (silicagel 47-61 micron mesh; elution with methanol/methylene chloride=1:9 involume) afforded the title compound (50 mg, 58% yield) as a colorlessamorphous solid, identical in all respects to the title compound of Step5, Example 5.

Preparation A 3-CHLORO-BENZO[d]ISOXAZOLE

This reactant is prepared by the method of H. Boshagen, Chem. Berichte,100, 3326-3330 (1967).

Preparation B 3-CHLORO-5-FLUOROBENZO[d]ISOXAZOLE

Step 1

5-Fluoro-2-hydroxy-benzoic acid ethyl ester [Buu-Hoi, et. al., J. Org.Chem., 19, 1617-1619 (1954)]

To a solution of 5-fluorosalicylic acid (50 g) in absolute ethanol (500ml), concentrated sulfuric acid (10 ml) was cautiously added. Thesolution was heated at 90° C. for 72 hours. The solvent was removed invacuo, and the viscous residue was made basic (final pH=9) byportionwise addition of saturated aqueous sodium bicarbonate. Thesolution was then extracted with three 200 ml portions of methylenechloride. The combined organic extracts were dried (anhydrous sodiumsulfate) and concentrated in vacuo to afford the title compound(quantitative yield) as a viscous colorless oil.

Step 2

5-Fluoro-2,N-dihydroxy-benzamide [A. Ostaszynski, Bull. Acad. Pol. Sci.Ser. Sci. Chim., 8, 591-597 (1960)]

To a well-stirred solution of hydroxylamine hydrochloride (31.3 g, 0.45mol) in water (180 ml), a solution of sodium hydroxide (41.5 g, 1.04mol) in water (360 ml) was added. To the resulting solution, a solutionof the Step 1 title compound (55.4 g, 0.30 mol) in 1,4-dioxane (180 ml)was added dropwise over 20 minutes. The reaction was stirred at ambienttemperature for 18 hours. The 1,4-dioxane solvent was removed in vacuo,and the remaining aqueous solution was acidified (to pH 2) by additionof concentrated hydrochloric acid. The resulting precipitate wasfiltered, and the filter cake was air dried to afford the title compound(quantitative yield) as a colorless amorphous solid.

Step 3

3-Hydroxy-5-fluoro-benzo[d]isoxazole

To a vigorously refluxing solution of the title compound of Step 2 (96g, 0.56 mol) in tetrahydrofuran (1.6 L), a tetrahydrofuran (3.2 L)solution of 1,1′-carbonyl dimidazole (183 g, 1.13 mol) was added in aslow stream over a 4 hour period. The solution was stirred while thesolvent was removed by atmospheric distillation. The resulting oilyresidue was chilled with an ice bath. Water (650 ml) was added slowly(causing considerable gas evolution), followed by slow addition ofconcentrated hydrochloric acid until the pH was 2. The mixture was thenstirred for 18 hours, yielding a granulated colorless solid. Filtration,washing of the filter cake with water, and in vacuo drying afforded thetitle compound as a colorless solid (73 g; 85% yield).

¹H NMR (400 MHz, CDCl₃) delta 7.29-7.45 (m, 2H), 7.25 (m, 1H) ppm.

Step 4

3-Chloro-5-fluoro-benzo[d]isoxazole

To a mixture of the Step 3 title compound (1.68 g, 11 mmol) andphosphous oxychloride (2.46 ml, 26 mmol), pyridine (979 μl) was added.The resulting reaction mixture was heated at 100° C. for 18 hours.Cooled to ambient temperature, the mixture was cautiously added to water(15 ml). After 5 minutes of stirring, a solid precipitate formed, whichwas filtered. The filter cake was washed with water (5 ml) and dried invacuo, affording the title compound as a tan amorphous solid (973 mg,52% yield).

¹H NMR (400 MHz, CD₃OD) δ 7.50 (m, 2H), 7.72 (m, 1H).

1. A pharmaceutical composition for treating a disorder or conditionthat can be treated or prevented by modulating serotonergicneurotransmission in a mammal, comprising: a) a pharmaceuticallyacceptable carrier; b)(7S,9aS)-cis-2Benzo[d]isoxazol-3-yl-7-(3-pyrrolidin-1-ylmethyl-phenoxymethyl)-octahydro-pyrido-[1,2-a]pyrazine;and c) sertraline or a pharmaceutically acceptable salt thereof; whereinthe amount of b) and the amount of c) are such that the combination iseffective in treating such disorder or condition.
 2. A method fortreating a disorder or condition that can be treated by modulatingserotonergic neurotransmisslon in a mammal, comprising administering toa mammal requiring such treatment or prevention: a)(7S,9aS)-cis-2Benzo[d]isoxazol-3-yl-7-(3-pyrrolidin-1-ylmethyl-phenoxymethyl)-octahydro-pyrido-[1,2-a]pyrazine;and b) sertraline or a pharmaceutically acceptable salt thereof; whereinthe amount of a) and the amount of b) are such that the combination iseffective in treating such disorder or condition.
 3. A method fortreating a disorder or condition selected from depression or generalizedanxiety disorder in a mammal, comprising administering to a mammalrequiring such treatment: a)(7S,9aS)-cis-2Benzo[d]isoxazol-3-yl-7-(3-pyrrolidin-1-ylmethyl-phenoxymethyl)-octahydro-pyrido-[1,2-a]pyrazine;and b) sertraline or a pharmaceutically acceptable salt thereof; whereinthe amount of a) and the amount of b) are such that the combination iseffective in treating such disorder or condition.